TW201643157A - Gdf-8抑制劑 - Google Patents
Gdf-8抑制劑 Download PDFInfo
- Publication number
- TW201643157A TW201643157A TW105104992A TW105104992A TW201643157A TW 201643157 A TW201643157 A TW 201643157A TW 105104992 A TW105104992 A TW 105104992A TW 105104992 A TW105104992 A TW 105104992A TW 201643157 A TW201643157 A TW 201643157A
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- haloalkyl
- bipyridyl
- imidazo
- het
- Prior art date
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- 108010056852 Myostatin Proteins 0.000 title claims description 56
- 102000004472 Myostatin Human genes 0.000 title claims 5
- 239000003112 inhibitor Substances 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 490
- 238000000034 method Methods 0.000 claims abstract description 217
- 150000003839 salts Chemical class 0.000 claims abstract description 75
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 52
- 201000010099 disease Diseases 0.000 claims abstract description 45
- 229940002612 prodrug Drugs 0.000 claims abstract description 40
- 239000000651 prodrug Substances 0.000 claims abstract description 40
- 239000012453 solvate Substances 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 27
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 178
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 173
- -1 C 1 -C 6 alkyl Chemical group 0.000 claims description 172
- 229910052736 halogen Inorganic materials 0.000 claims description 143
- 150000002367 halogens Chemical class 0.000 claims description 143
- 229910052739 hydrogen Inorganic materials 0.000 claims description 125
- 239000001257 hydrogen Substances 0.000 claims description 121
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 115
- 150000002431 hydrogen Chemical class 0.000 claims description 93
- 125000001188 haloalkyl group Chemical group 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 125000002619 bicyclic group Chemical group 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 31
- 210000003205 muscle Anatomy 0.000 claims description 28
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 24
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 23
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 19
- ZMBYQTGAXZOMOO-UHFFFAOYSA-N imidazo[1,2-a]pyridine-3-carboxamide Chemical compound C1=CC=CN2C(C(=O)N)=CN=C21 ZMBYQTGAXZOMOO-UHFFFAOYSA-N 0.000 claims description 17
- 201000006938 muscular dystrophy Diseases 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 16
- 241000124008 Mammalia Species 0.000 claims description 15
- 239000003085 diluting agent Substances 0.000 claims description 15
- 239000003937 drug carrier Substances 0.000 claims description 13
- DREUPRFRJOSEAM-UHFFFAOYSA-N imidazo[1,2-a]pyridine-3-carbonitrile Chemical compound C1=CC=CN2C(C#N)=CN=C21 DREUPRFRJOSEAM-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 claims description 12
- 208000001132 Osteoporosis Diseases 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical class NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims description 10
- 238000002560 therapeutic procedure Methods 0.000 claims description 10
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 10
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 9
- 210000000988 bone and bone Anatomy 0.000 claims description 9
- 208000011580 syndromic disease Diseases 0.000 claims description 9
- PEKUAWGDFMCYPI-UHFFFAOYSA-N 6-[2-(6-methylpyridin-2-yl)pyridin-3-yl]imidazo[1,2-a]pyridine Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C=1)C=CN=2 PEKUAWGDFMCYPI-UHFFFAOYSA-N 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 8
- 208000026062 Tissue disease Diseases 0.000 claims description 7
- 210000000577 adipose tissue Anatomy 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 208000001076 sarcopenia Diseases 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- KWJNYONYDWUEKL-UHFFFAOYSA-N CC1=CC=CC(=N1)C1=NC=CC=C1C1=C2C3=CC=CCC3=NC2=CC=C1 Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C1=C2C3=CC=CCC3=NC2=CC=C1 KWJNYONYDWUEKL-UHFFFAOYSA-N 0.000 claims description 5
- 206010006895 Cachexia Diseases 0.000 claims description 5
- 208000011623 Obstructive Lung disease Diseases 0.000 claims description 5
- 230000037182 bone density Effects 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 208000018360 neuromuscular disease Diseases 0.000 claims description 5
- 235000005152 nicotinamide Nutrition 0.000 claims description 5
- 239000011570 nicotinamide Substances 0.000 claims description 5
- XBRZTHDHIMYWLN-UHFFFAOYSA-N 6-[2-(6-methylpyridin-2-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-3-carbonitrile Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C=1)C(=CN=2)C#N XBRZTHDHIMYWLN-UHFFFAOYSA-N 0.000 claims description 4
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 4
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- 208000029578 Muscle disease Diseases 0.000 claims description 4
- 208000021642 Muscular disease Diseases 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 208000014674 injury Diseases 0.000 claims description 4
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 4
- 230000008733 trauma Effects 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- PEFYDHOUMOOYOE-UHFFFAOYSA-N 6-(2-pyridin-2-ylpyridin-3-yl)quinazolin-4-amine Chemical compound N1=C(C(=CC=C1)C=1C=C2C(=NC=NC2=CC=1)N)C1=NC=CC=C1 PEFYDHOUMOOYOE-UHFFFAOYSA-N 0.000 claims description 3
- DGFSIJYSSFFQNN-UHFFFAOYSA-N 6-[2-(6-methylpyridin-2-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C=1)C(=CN=2)C(=O)N DGFSIJYSSFFQNN-UHFFFAOYSA-N 0.000 claims description 3
- 208000000103 Anorexia Nervosa Diseases 0.000 claims description 3
- 208000002720 Malnutrition Diseases 0.000 claims description 3
- 206010047626 Vitamin D Deficiency Diseases 0.000 claims description 3
- 239000003098 androgen Substances 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 239000003862 glucocorticoid Substances 0.000 claims description 3
- 208000030159 metabolic disease Diseases 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 230000002028 premature Effects 0.000 claims description 3
- XMRIUEGHBZTNND-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1=CC=NC2=C(C(=O)N)C=NN21 XMRIUEGHBZTNND-UHFFFAOYSA-N 0.000 claims description 3
- HNYVPKNVKSTVJO-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound C1=CC=NC2=C(C(=O)O)C=NN21 HNYVPKNVKSTVJO-UHFFFAOYSA-N 0.000 claims description 3
- 230000001629 suppression Effects 0.000 claims description 3
- 235000000112 undernutrition Nutrition 0.000 claims description 3
- LVLOTYIMYWLIDK-UHFFFAOYSA-N 3-(4-fluorophenyl)-6-pyridin-4-ylpyrazolo[1,5-a]pyrimidine Chemical compound C1=CC(F)=CC=C1C1=C2N=CC(C=3C=CN=CC=3)=CN2N=C1 LVLOTYIMYWLIDK-UHFFFAOYSA-N 0.000 claims description 2
- GLVMHLFIFCVTSY-UHFFFAOYSA-N 6-[2-(4-fluoropyridin-2-yl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carbonitrile Chemical compound FC1=CC(=NC=C1)C1=NC=CC=C1C=1C=CC=2N(N=1)C(=CN=2)C#N GLVMHLFIFCVTSY-UHFFFAOYSA-N 0.000 claims description 2
- IPTBQVPQHNXVFY-UHFFFAOYSA-N 6-[2-(5-fluoro-6-methylpyridin-2-yl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carbonitrile Chemical compound FC=1C=CC(=NC=1C)C1=NC=CC=C1C=1C=CC=2N(N=1)C(=CN=2)C#N IPTBQVPQHNXVFY-UHFFFAOYSA-N 0.000 claims description 2
- YZIMZSCGXKSDIL-UHFFFAOYSA-N 6-[2-(5-methylpyridin-2-yl)pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide Chemical compound CC=1C=CC(=NC=1)C1=NC=CC=C1C=1C=CC=2N(N=1)C(=CN=2)C(=O)N YZIMZSCGXKSDIL-UHFFFAOYSA-N 0.000 claims description 2
- LBHOAKVBSFBSEX-UHFFFAOYSA-N 6-[2-(6-methoxypyridin-2-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide Chemical compound COC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C=1)C(=CN=2)C(=O)N LBHOAKVBSFBSEX-UHFFFAOYSA-N 0.000 claims description 2
- ZORXRGAPSQEFGA-UHFFFAOYSA-N 6-[2-(6-methylpyridin-2-yl)pyridin-3-yl]-[1,2,4]triazolo[1,5-a]pyridine Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C=1)N=CN=2 ZORXRGAPSQEFGA-UHFFFAOYSA-N 0.000 claims description 2
- XHPVHXBWWXRLEP-UHFFFAOYSA-N 6-[2-(6-methylpyridin-2-yl)pyridin-3-yl]quinazolin-4-amine Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=C2C(=NC=NC2=CC=1)N XHPVHXBWWXRLEP-UHFFFAOYSA-N 0.000 claims description 2
- LXJVYERTNJFFFB-UHFFFAOYSA-N 6-[2-[6-(difluoromethyl)pyridin-2-yl]pyridin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide Chemical compound FC(C1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(N=1)C(=CN=2)C(=O)N)F LXJVYERTNJFFFB-UHFFFAOYSA-N 0.000 claims description 2
- NFOWFTIOEIHVID-UHFFFAOYSA-N 6-[4-(difluoromethyl)-2-(6-methylpyridin-2-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-3-carbonitrile Chemical compound FC(C1=C(C(=NC=C1)C1=NC(=CC=C1)C)C=1C=CC=2N(C=1)C(=CN=2)C#N)F NFOWFTIOEIHVID-UHFFFAOYSA-N 0.000 claims description 2
- 230000008901 benefit Effects 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 230000003412 degenerative effect Effects 0.000 claims description 2
- 230000002710 gonadal effect Effects 0.000 claims description 2
- YLXWTAXPOOYRSL-UHFFFAOYSA-N imidazo[1,2-b]pyridazine-3-carbonitrile Chemical compound C1=CC=NN2C(C#N)=CN=C21 YLXWTAXPOOYRSL-UHFFFAOYSA-N 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- DGXAOSOMFMODCF-UHFFFAOYSA-N pyrido[3,2-d]pyrimidin-4-amine Chemical compound C1=CN=C2C(N)=NC=NC2=C1 DGXAOSOMFMODCF-UHFFFAOYSA-N 0.000 claims 4
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 claims 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- 150000001925 cycloalkenes Chemical class 0.000 claims 2
- NBEWMBVUHSPONV-UHFFFAOYSA-N quinazolin-4-amine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1=CC=C2C(N)=NC=NC2=C1 NBEWMBVUHSPONV-UHFFFAOYSA-N 0.000 claims 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 2
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- WRPFUIWJWHZDCJ-UHFFFAOYSA-N 4-[2-(6-methylpyridin-2-yl)pyridin-3-yl]quinoline Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C1=CC=NC2=CC=CC=C12 WRPFUIWJWHZDCJ-UHFFFAOYSA-N 0.000 claims 1
- IYAZEYWWCVJQQK-UHFFFAOYSA-N CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(N1)C(=CN2)C(=O)N.CC2=CC=CC(=N2)C2=NC=CC=C2C=2C=CC=1N(N2)C(=CN1)C#N Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(N1)C(=CN2)C(=O)N.CC2=CC=CC(=N2)C2=NC=CC=C2C=2C=CC=1N(N2)C(=CN1)C#N IYAZEYWWCVJQQK-UHFFFAOYSA-N 0.000 claims 1
- XSQMJCHSDMZRFE-UHFFFAOYSA-N CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(N1)C(=CN2)C(=O)O.CC=2N=C1N(C=C(C=C1)C=1C(=NC=CC1)C1=NC(=CC=C1)C)C2C(=O)N Chemical compound CC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(N1)C(=CN2)C(=O)O.CC=2N=C1N(C=C(C=C1)C=1C(=NC=CC1)C1=NC(=CC=C1)C)C2C(=O)N XSQMJCHSDMZRFE-UHFFFAOYSA-N 0.000 claims 1
- QOEYIVHGERGLFU-UHFFFAOYSA-N FC(C1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C(=O)N)(F)F.COC2=CC=CC(=N2)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C#N Chemical compound FC(C1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C(=O)N)(F)F.COC2=CC=CC(=N2)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C#N QOEYIVHGERGLFU-UHFFFAOYSA-N 0.000 claims 1
- VIQUZGMJVPASJF-UHFFFAOYSA-N FC1=CC(=NC=C1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C#N.FC=2C=CC(=NC2C)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C#N Chemical compound FC1=CC(=NC=C1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C#N.FC=2C=CC(=NC2C)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C#N VIQUZGMJVPASJF-UHFFFAOYSA-N 0.000 claims 1
- JMSSBXWFEQTNHJ-UHFFFAOYSA-N FC1=CC(=NC=C1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C(=O)N.FC=2C=CC(=NC2)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C(=O)N Chemical compound FC1=CC(=NC=C1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C(=O)N.FC=2C=CC(=NC2)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C(=O)N JMSSBXWFEQTNHJ-UHFFFAOYSA-N 0.000 claims 1
- AGFVFOBJWDIEAV-UHFFFAOYSA-N FC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C#N.C2(CC2)C2=CC=CC(=N2)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C(=O)N Chemical compound FC1=CC=CC(=N1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C#N.C2(CC2)C2=CC=CC(=N2)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C(=O)N AGFVFOBJWDIEAV-UHFFFAOYSA-N 0.000 claims 1
- CICCIAANPRXACT-UHFFFAOYSA-N FC=1C=CC(=NC1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C#N.FC=2C=CC(=NC2C)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C(=O)N Chemical compound FC=1C=CC(=NC1)C1=NC=CC=C1C=1C=CC=2N(C1)C(=CN2)C#N.FC=2C=CC(=NC2C)C2=NC=CC=C2C=2C=CC=1N(C2)C(=CN1)C(=O)N CICCIAANPRXACT-UHFFFAOYSA-N 0.000 claims 1
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 claims 1
- ZNRNNIUKMCIEAZ-UHFFFAOYSA-N N-(2,2-difluoroethyl)-6-[2-(6-methylpyridin-2-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide 6-[2-(6-methylpyridin-2-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-3-carboxylic acid Chemical compound Cc1cccc(n1)-c1ncccc1-c1ccc2ncc(C(O)=O)n2c1.Cc1cccc(n1)-c1ncccc1-c1ccc2ncc(C(=O)NCC(F)F)n2c1 ZNRNNIUKMCIEAZ-UHFFFAOYSA-N 0.000 claims 1
- OLANRYCHDPJMJQ-UHFFFAOYSA-N N-methyl-5-[2-[6-(trifluoromethyl)pyridin-2-yl]pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound CNC(=O)C=1C=NN2C=1N=C(C=C2)C=1C(=NC=CC=1)C1=NC(=CC=C1)C(F)(F)F OLANRYCHDPJMJQ-UHFFFAOYSA-N 0.000 claims 1
- RJALCGMLLASKMR-UHFFFAOYSA-N ethyl 5-[2-[6-(trifluoromethyl)pyridin-2-yl]pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate 5-[2-(5-fluoro-6-methylpyridin-2-yl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile Chemical compound Cc1nc(ccc1F)-c1ncccc1-c1ccn2ncc(C#N)c2n1.CCOC(=O)c1cnn2ccc(nc12)-c1cccnc1-c1cccc(n1)C(F)(F)F RJALCGMLLASKMR-UHFFFAOYSA-N 0.000 claims 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 1
- DOGXPDFZEQXZDS-UHFFFAOYSA-N imidazo[1,2-a]pyridine-3-carboxylic acid Chemical compound C1=CC=CN2C(C(=O)O)=CN=C21 DOGXPDFZEQXZDS-UHFFFAOYSA-N 0.000 claims 1
- 125000003566 oxetanyl group Chemical group 0.000 claims 1
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical compound N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 claims 1
- RRHORVAOECWFPT-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carbonitrile Chemical compound C1=CC=NC2=C(C#N)C=NN21 RRHORVAOECWFPT-UHFFFAOYSA-N 0.000 claims 1
- GZPHSAQLYPIAIN-DOMIDYPGSA-N pyridine-3-carbonitrile Chemical compound N#[14C]c1cccnc1 GZPHSAQLYPIAIN-DOMIDYPGSA-N 0.000 claims 1
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims 1
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 abstract description 58
- 230000011664 signaling Effects 0.000 abstract description 17
- 101000886562 Homo sapiens Growth/differentiation factor 8 Proteins 0.000 abstract description 8
- 150000001204 N-oxides Chemical class 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 228
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 192
- 238000005481 NMR spectroscopy Methods 0.000 description 150
- 238000002474 experimental method Methods 0.000 description 133
- 238000002953 preparative HPLC Methods 0.000 description 105
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Abstract
本發明揭示2,2'-聯吡啶基化合物以及其醫藥組合物及使用方法。一個實施例為具有以下結構之化合物
□及其醫藥學上可接受之鹽、前藥及N-氧化物(及其溶劑合物及水合物),其中R1、Z及n如本文所描述。在某些實施例中,本文所揭示之化合物抑制GDF8,且可用於藉由阻斷GDF8信號傳導來治療疾病。
Description
本發明係關於醫藥學上活性化合物及其使用方法。特定言之,本發明係關於激酶抑制劑。在一個態樣中,該等化合物亦抑制經由跨膜激酶受體進行信號傳導之細胞激素的信號傳導,該等細胞激素諸如TGF-β1、生長分化因子-8(GDF-8)及TGF-β之其他成員、活化素、抑制素、骨形態生成蛋白及苗勒氏管抑制物質。抑制劑適用於治療發炎性病症,諸如發炎性或阻塞性氣管疾病,諸如肺高血壓、肺纖維化、肝纖維化;及癌症。抑制劑特別適用於診斷、預防或治療其中肌肉組織增加將在治療學上有益人類或動物病症。例示性病症包括神經肌肉病症(例如肌肉營養不良及肌肉萎縮症)充血性阻塞性肺病、肌肉萎縮症候群、肌肉減少症及惡病體質;脂肪組織病症(諸如肥胖);2型糖尿病;及骨骼退化疾病(諸如骨質疏鬆)。
生長及分化因子-8(GDF-8)(亦稱為肌肉抑制素)及TGF-β1為結構上相關生長因子之轉型生長因子-β(TGF-β)超級家族的成員,其均具有生理學上至關重要之生長調控及形態生成特性(Kingsley等人(1994)Genes Dev.,8:133-46;Hoodless等人(1998)Curr.Topics Microbiol.Immunol.,228:235-72)。舉例而言,TGF-β1信號傳導之活化及細胞外基質之擴張為纖維化病症(諸如涉及慢性腎病及血管疾病之纖維化病症)出現及發展的早期及持續性促成因素。Border W.A.等
人,N.Engl.J.Med.,1994;331(19),1286-92。GDF-8為骨胳肌肉質量之負調控劑,且鑑別調控其生物活性之因子受到大量關注。舉例而言,GDF-8在發育中及成人骨胳肌肉中高度表現。轉殖基因小鼠中GDF-8剔除式突變之特徵在於骨胳肌肉之顯著肥大及增生(McPherron等人(1997)Nature,387:83-90)。骨胳肌肉質量中之類似增加在牛中天然存在之GDF-8突變中顯而易見(Ashmore等人(1974)Growth,38:501 507;Swatland及Kieffer(1994)J.Anim.Sci.,38:752-757;McPherron及Lee(1997)Proc.Natl.Acad.Sci.USA,94:12457-12461;及Kambadur等人(1997)Genome Res.,7:910-915)。因為GDF-8在發育中及成人肌肉兩者中表現,所以不清楚其是在發育期間還是在成人中調控肌肉質量。因此,自科學及治療性視角,GDF-8是否在成人中調控肌肉質量之問題至關重要。近期研究亦已展示,與人類中HIV感染相關聯之肌肉萎縮伴隨有GDF-8蛋白質表現增加(Gonzalez-Cadavid等人(1998)PNAS,95:14938-43)。另外,GDF-8可調節肌肉特異性酶(例如肌酸激酶)之產生及調節肌母細胞增殖(WO 00/43781)。
多種人類及動物病症與肌肉組織之損失或功能性損傷相關聯,包括肌肉營養不良、肌肉萎縮症、充血性阻塞性肺病、肌肉萎縮症候群、肌肉減少症及惡病體質。迄今為止,用於此等病症之可靠或有效療法存在非常少。然而,與此等病症相關聯之糟糕症狀可藉由採用在患有該等病症之患者中增加肌肉組織量的療法來實質上減少。雖然未治癒該等病狀,但此類療法將顯著地改良此等患者之生活品質且可改善此等疾病之一些影響。因此,在此項技術中需要鑑別可有助於在患有此等病症之患者中使肌肉組織總體增加的新療法。
除其在骨胳肌肉中之生長調控及形態生成特性以外,GDF-8亦可涉及多種其他生理學過程,包括在2型糖尿病及脂肪組織病症(諸如肥胖)出現中之葡萄糖內穩定。舉例而言,GDF-8調節分化成脂肪細胞
之前脂肪細胞分化(Kim等人(2001)BBRC,281:902-906)。
亦存在多種與骨流失相關聯之病狀,包括骨質疏鬆,尤其在老年及/或停經後女性中存在。目前可供此等病狀使用之療法藉由抑制骨骼再吸收來起作用。促進新骨骼形成之療法將為此等療法之所需替代方案或附加。
如同TGF-β-1、TGF-β-2及TGF-β-3,GDF-8蛋白質合成為由胺基端原肽及羧基端成熟結構域組成之前驅蛋白(McPherron及Lee,(1997)Proc.Natl.Acad.Sci.USA,94:12457-12461)。在裂解之前,前驅體GDF-8蛋白質形成均二聚體。胺基端原肽隨後與成熟結構域裂解。裂解之原肽可保持非共價結合於成熟結構域二聚體,使其生物活性失活(Miyazono等人(1988)J.Biol.Chem.,263:6407-6415;Wakefield等人(1988)J.Biol.Chem.,263;7646-7654;及Brown等人(1990)Growth Factors,3:35-43)。咸信兩個GDF-8前肽結合於GDF-8成熟二聚體(Thies等人(2001)Growth Factors,18:251-259)。歸因於此失活特性,原肽稱為「潛伏相關肽」(LAP),且成熟結構域及原肽之複合物通常稱為「小潛伏性複合物」(Gentry及Nash(1990)Biochemistry,29:6851-6857;Derynck等人(1995)Nature,316:701-705;及Massague(1990)Ann.Rev.Cell Biol.,12:597-641)。亦已知其他蛋白質結合於GDF-8或結構上相關蛋白質,且抑制其生物活性。此類抑制性蛋白質包括卵泡抑素且可能包括卵泡抑素相關蛋白質(Gamer等人(1999)Dev.Biol.,208:222-232)。咸信當移除原肽時,成熟結構域以均二聚體形式具有活性。
GDF-8在序列及功能中跨物種高度保守。鼠類及人類GDF-8之胺基酸序列一致,mRNA表現之模式亦一致(McPherron等人(1997)Nature 387:83-90;Gonzalez-Cadavid等人(1998)Proc.Natl.Acad.Sci.USA 95:14938-14943)。序列及功能之此保守性表明,抑制人類
中GDF-8之作用很可能與抑制小鼠中GDF-8類似。
GDF-8涉及許多關鍵性生物過程之調控。歸因於其在此等過程中之關鍵功能,GDF-8可為治療性干預之所需目標。
舉例而言,美國專利第7,320,789號展示,小鼠模型中之GDF-8抗體可增加肌肉強度(例如,用於治療肌肉減少症),增加營養不良肌肉中之肌肉質量及強度(例如,用於治療杜興氏肌肉營養不良(Duchenne's muscular dystrophy)),增加骨質量及骨密度(例如,用於預防及治療骨質疏鬆),加強骨骼癒合(例如,用於治療確立之肌肉或骨骼退化疾病(例如骨折修復及脊柱融合,預防骨質量衰退,與雌激素不足相關聯之微架構及強度,增加小樑骨密度),且適用於治療代謝障礙,諸如2型糖尿病、葡萄糖耐量異常、代謝症候群(例如症候群X)、由外傷(例如灼傷)誘發之胰島素抗性及脂肪組織病症(例如肥胖)。
特定言之,如上文所論述,抑制GDF-8之活性的治療劑可用於治療其中肌肉組織增加將在治療學上有益之人類或動物病症,尤其肌肉及脂肪組織病症、骨骼退化疾病、神經肌肉病症及糖尿病。
在一個態樣中,本發明係關於式(I)化合物,
及其醫藥學上可接受之鹽,其中n、R1及Z在本文中定義。
在另一態樣中,揭示醫藥組合物,其包含式(I)之化合物或式(I)之化合物的醫藥學上可接受之鹽及醫藥學上可接受之載劑、賦形劑或稀釋劑。
在另一態樣中,揭示用於抑制細胞中GDF-8之方法,其包含使該
細胞與有效量的式(I)之化合物;或式(I)之化合物的醫藥學上可接受之鹽;或包含式(I)之化合物或式(I)之化合物的醫藥學上可接受之鹽及醫藥學上可接受之載劑、賦形劑或稀釋劑的醫藥組合物接觸。
在另一態樣中,揭示用於治療患有疾病或病症之患者的方法,其中該患者將會因肌肉組織質量或強度提高而受到醫療效益,該等方法包含向患者投與治療有效量的式(I)之化合物;或式(I)之化合物的醫藥學上可接受之鹽;或包含式(I)之化合物或式(I)之化合物的醫藥學上可接受之鹽及醫藥學上可接受之載劑、賦形劑或稀釋劑的醫藥組合物。
在另一態樣中,揭示用於在哺乳動物中增加肌肉質量之方法,其包含投與治療有效量的式(I)之化合物;或式(I)之化合物的醫藥學上可接受之鹽;或包含式(I)之化合物或式(I)之化合物的醫藥學上可接受之鹽及醫藥學上可接受之載劑、賦形劑或稀釋劑的醫藥組合物。
在另一態樣中,揭示用於在哺乳動物中增加肌肉強度之方法,其包含投與治療有效量的式(I)之化合物或醫藥學上可接受之鹽;或包含式(I)之化合物醫藥學上可接受之鹽及醫藥學上可接受之載劑、賦形劑或稀釋劑的醫藥組合物。
在另一態樣中,揭示用於在有需要之患者中增加小樑骨密度的方法,其包含投與治療有效量的式(I)之化合物或醫藥學上可接受之鹽;或包含式(I)之化合物醫藥學上可接受之鹽及醫藥學上可接受之載劑、賦形劑或稀釋劑的醫藥組合物。
在另一態樣中,出於研究GDF-8抑制對受GDF-8活性影響之生物過程的作用的目的,本文所揭示之化合物及組合物適用於活體外、離體及活體內抑制TGF-β超級家族細胞激素,包括(但不限於)TGF-β、GDF-8、活化素-A或其組合。根據此態樣之實施例包含在促進本文所描述之化合物或組合物與GDF-8之間接觸的情況下接觸或投與(視需
要)該化合物或組合物,由此促進該化合物或組合物對GDF-8之抑制。視情況,活體外、離體及活體內抑制GDF-8之方法藉由用於測定抑制之作用的適當分析來追蹤。此態樣之一個實施例包含一種活體內抑制GDF-8之方法,其包含向哺乳動物(諸如人類)投與抑制GDF-8有效量的本文所揭示之化合物或組合物。
在一個態樣中,本發明包含抑制一或多種激酶,諸如TGF-β受體超級家族激酶之化合物。因此且不受任何特定理論顯示,本發明所揭示之化合物抑制TGF-β超級家族細胞激素,諸如TGF-β、活化素A、GDF-8或其組合之信號傳導。
在此第一態樣之實施例I0中,該等化合物具有結構式(I°):
或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物,其中n為1、2、3或4;R1為氫、鹵素、氰基、硝基、C1-6烷基、C1-6鹵烷基、C3-8環烷基、C3-8環烯基、雜環基、芳基、雜芳基、-Ra或-C1-6烷基-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-O(CH2)mC(O)NRS1RS1、-N(RS1)C(O)ORS1、-N(R)C(O)NRS1RS1、-
N(RS1)S(O)2NRS1RS1或-N(RS1)S(O)2RS1;其中m為0、1、2或3;且其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代;p為1、2、3或4;R2為氫、鹵素、氰基、硝基、C1-6烷基、C1-6鹵烷基、C3-8環烷基、C3-8環烯基、雜環基、芳基、雜芳基、-Rb或-C1-6烷基-Rb,其中Rb為-ORS4、-SRS4、-NRS4RS4、-C(O)RS4、-C(O)ORS4、-C(O)NRS4RS4、-S(O)2NRS4RS4、-OC(O)RS4、-N(RS4)C(O)RS4、-OC(O)ORS4、-O(CH2)qC(O)NRS4RS4、-N(RS4)C(O)ORS4、-N(R)C(O)NRS4RS4、-N(RS4)S(O)2NRS4RS4或-N(RS4)S(O)2RS4;其中q為0、1、2或3;且其中各RS4獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代;Z為
式之稠合雙環,其中
環A為Ar或6員Het,環B為5員或6員Het,其中Z視情況經一個或兩個-RZ基團取代,該或該等-RZ基團各自獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS2、-
SRS2、-NRS2 2、-C(O)RS2、-C(O)ORS2、-C(O)NRS2 2、-S(O)2NRS2 2、-S(O)2RS2、-OC(O)RS2、-N(RS2)C(O)RS2、-OC(O)ORS2、-OC(O)NRS2 2、-N(RS2)C(O)ORS2、-N(RS2)C(O)NRS2 2、-N(RS2)S(O)2RS2、-OP(O)(ORS2)2或-CH2-OP(O)(ORS2),其中各烷基、鹵烷基及烷氧基視情況經一個或兩個-RZ2基團取代;其中各RS2獨立地為氫、C1-C6烷基、C1-C6鹵烷基、C1-C6烷基-O-C1-C6烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代;且各-RZ2獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS3、-SRS3、-NRS3 2、-C(O)RS3、-C(O)ORS3、-C(O)NRS3 2、-S(O)2NRS3 2、-S(O)2RS3、-OC(O)RS3、-N(RS3)C(O)RS3、-OC(O)ORS3、-OC(O)NRS3 2、-N(RS3)C(O)ORS3、-N(RS3)C(O)NRS3 2、-N(RS3)S(O)2RS3、-OP(O)(ORS3)2或-CH2-OP(O)(ORS3);且其中各RS3獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
在此第一態樣之實施例I1中,該等化合物具有結構式(I):
或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物,其中
n為1、2、3或4;R1為氫、鹵素、氰基、硝基、C1-6烷基、C1-6鹵烷基、C3-8環烷基、C3-8環烯基、雜環基、芳基、雜芳基、-Ra或-C1-6烷基-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-O(CH2)mC(O)NRS1RS1、-N(RS1)C(O)ORS1、-N(R)C(O)NRS1RS1、-N(RS1)S(O)2NRS1RS1或-N(RS1)S(O)2RS1;其中m為0、1、2或3;且其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代;Z為
式之稠合雙環,其中
環A為Ar或6員Het,環B為5員或6員Het,其中Z視情況經一個或兩個-RZ基團取代,該或該等-RZ基團各自獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS2、-SRS2、-NRS2 2、-C(O)RS2、-C(O)ORS2、-C(O)NRS2 2、-S(O)2NRS2 2、-S(O)2RS2、-OC(O)RS2、-N(RS2)C(O)RS2、-OC(O)ORS2、-OC(O)NRS2 2、-N(RS2)C(O)ORS2、-N(RS2)C(O)NRS2 2、-N(RS2)S(O)2RS2、-OP(O)(ORS2)2或-CH2-OP(O)(ORS2),其中各烷基、鹵烷基及烷氧基視情況經一個或兩個-RZ2基團取代;其中各RS2獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-
Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代;且各-RZ2獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS3、-SRS3、-NRS3 2、-C(O)RS3、-C(O)ORS3、-C(O)NRS3 2、-S(O)2NRS3 2、-S(O)2RS3、-OC(O)RS3、-N(RS3)C(O)RS3、-OC(O)ORS3、-OC(O)NRS3 2、-N(RS3)C(O)ORS3、-N(RS3)C(O)NRS3 2、-N(RS3)S(O)2RS3、-OP(O)(ORS3)2或-CH2-OP(O)(ORS3);且其中各RS3獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
在實施例I'中,該等化合物為實施例I1之化合物,其限制條件為該化合物不為國際公開案第WO 2014/055955 A1號中明確敍述之任何化合物。
在實施例I"中,該等化合物為實施例Io之化合物,其限制條件為該化合物不為國際公開案第WO 2014/055955 A1號中明確敍述之任何化合物。
在實施例I2中,該等化合物為實施例I1之化合物,其限制條件為該化合物不為5-(6'-甲基-[2,2'-聯吡啶]-3-基)-1H-吲唑。
在實施例I2'中,該等化合物為實施例I0之化合物,其限制條件為該化合物不為5-(6'-甲基-[2,2'-聯吡啶]-3-基)-1H-吲唑。
在實施例I3中,該等化合物為實施例I1之化合物,其中Z為
式之稠合雙環,其中
環A為Ar或6員Het,環B為5員或6員Het,其中Z視情況經一個或兩個-RZ基團取代,該或該等-RZ基團各自獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS2、-SRS2、-NRS2 2、-C(O)RS2、-C(O)ORS2、-C(O)NRS2 2、-S(O)2NRS2 2、-S(O)2RS2、-OC(O)RS2、-N(RS2)C(O)RS2、-OC(O)ORS2、-OC(O)NRS2 2、-N(RS2)C(O)ORS2、-N(RS2)C(O)NRS2 2、-N(RS2)S(O)2RS2、-OP(O)(ORS2)2或-CH2-OP(O)(ORS2);其中各RS2獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
在實施例I4中,該等化合物為實施例I1之化合物,其中Z為
式之稠合雙環,其中
(1)環A為Ar或6員Het,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;其中Z視情況經一個或兩個-RZ基團取代。
在實施例I4中,該等化合物為實施例I1之化合物,其中n為1或2,且各R1獨立地為鹵素、C1-6烷基、C1-6鹵烷基或C3-8環烷基。
本發明進一步包含式(I)之亞屬,其中結構式(I)、n、R1及Z為如下文所定義的任何群或群之組合(例如,其中該化合物為如在上文實
施例中之任一者中所定義的結構式(I)之化合物,且Z為視情況經一個RZ基團取代之苯并咪唑基,其中RZ為鹵素;或該化合物為式(Ib),Z為群(2g),R1為群(1d)且n為群(3e)):
(1a)R1為氫、鹵素、氰基、硝基、C1-6烷基、C1-6鹵烷基、C3-8環烷基、C3-8環烯基、雜環基、芳基、雜芳基、-Ra或-C1-6烷基-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-
C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-O(CH2)mC(O)NRS1RS1、-N(RS1)C(O)ORS1、-N(R)C(O)NRS1RS1、-N(RS1)S(O)2NRS1RS1或-N(RS1)S(O)2RS1;其中m為0、1、2或3;且其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1b)R1如(1a)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1c)R1為氫、-Ra或-C1-6烷基-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-O(CH2)mC(O)NRS1RS1、-N(RS1)C(O)ORS1、-N(R)C(O)NRS1RS1、-N(RS1)S(O)2NRS1RS1或-N(RS1)S(O)2RS1;其中m為0、1、2或3;且其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1d)R1如(1c)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1e)R1為氫、鹵素、氰基、硝基、C1-6烷基、C1-6鹵烷基、-Ra或-C1-6烷基-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-O(CH2)mC(O)NRS1RS1、-N(RS1)C(O)ORS1、-N(R)C(O)NRS1RS1、-N(RS1)S(O)2NRS1RS1 or-N(RS1)S(O)2RS1;
其中m為0、1、2或3;且其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1f)R1如(1e)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1g)R1為氫、鹵素、氰基、硝基、C1-6烷基、C1-6鹵烷基、C3-8環烷基、C3-8環烯基、雜環基、芳基、雜芳基、-Ra或-C1-6烷基-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-N(RS1)C(O)ORS1、-N(R)C(O)NRS1RS1、-N(RS1)S(O)2NRS1RS1或-N(RS1)S(O)2RS1;其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1h)R1如(1g)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1i)R1為氫、鹵素、氰基、硝基、C1-6烷基、C1-6鹵烷基、-Ra或-C1-6烷基-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-N(RS1)C(O)ORS1;其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1j)R1如(1i)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1k)R1為氫、鹵素、氰基、C1-6烷基、-Ra或-C1-6烷基-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-N(RS1)C(O)ORS1;其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1l)R1如(1k)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1m)R1為氫、鹵素、氰基、C1-6烷基或-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-N(RS1)C(O)ORS1;其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1n)R1如(1m)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1o)R1為氫或-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-N(RS1)C(O)ORS1;其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1p)R1如(1o)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1q)R1為鹵素、鹵素、氰基、C1-6烷基或-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-N(RS1)C(O)ORS1;其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1r)R1如(1q)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1s)R1為氫或-Ra,其中Ra為-ORS1、-SRS1、-NRS1RS1、-C(O)RS1、-C(O)ORS1、-C(O)NRS1RS1、-S(O)2NRS1RS1、-OC(O)RS1、-N(RS1)C(O)RS1、-OC(O)ORS1、-N(RS1)C(O)ORS1;其中各RS1獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(1t)R1如(1s)中所描述,其中RS1獨立地為氫或C1-C6烷基。
(1u)R1為氫、鹵素、氰基、硝基、C1-6烷基、C1-6鹵烷基、C3-8環烷基、C3-8環烯基、雜環基、芳基或雜芳基。
(1v)R1為氫、C3-8環烷基、C3-8環烯基、雜環基、芳基或雜芳基。
(1w)R1為氫、鹵素、氰基、硝基、C1-6烷基或C1-6鹵烷基。
(1x)R1為鹵素、氰基、硝基、C1-6烷基或C1-6鹵烷基。
(1y)R1為氫、鹵素、氰基或硝基。
(1z)R1為氫、鹵素、硝基、C1-6烷基或C1-6鹵烷基。
(1aa)R1為氫、鹵素、氰基、C1-6烷基或C1-6鹵烷基。
(1bb)R1為氫、鹵素、氰基、硝基或C1-6鹵烷基。
(1cc)R1為氫、氰基、硝基、C1-6烷基或C1-6鹵烷基。
(1dd)R1為氫、氰基、C1-6烷基或C1-6鹵烷基。
(1ee)R1為氫、鹵素、C1-6烷基或C1-6鹵烷基。
(1ff)R1為氫、鹵素或C1-6烷基。
(1gg)R1為氫或C1-6烷基。
(1hh)R1為氫或鹵素。
(1ii)R1為鹵素或C1-6烷基。
(1jj)R1為鹵素或C1-4烷基。
(1kk)R1為鹵素或C1-4烷基。
(1ll)R1為氫、鹵素或甲基。
(1mm)R1為鹵素或甲基。
(1nn)R1為氫、氟或甲基。
(1oo)R1為氟或甲基。
(1pp)R1為氫、氟。
(1qq)R1為氟。
(1rr)R1為氫、甲基。
(1ss)R1為甲基。
(1tt)R1為氫。
(2a)Z為
式之稠合雙環,其中
環A為Ar或6員Het,環B為5員或6員Het,其中
Z視情況經一個或兩個-RZ基團取代,該或該等-RZ基團各自獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS2、-SRS2、-NRS2 2、-C(O)RS2、-C(O)ORS2、-C(O)NRS2 2、-S(O)2NRS2 2、-S(O)2RS2、-OC(O)RS2、-N(RS2)C(O)RS2、-OC(O)ORS2、-OC(O)NRS2 2、-N(RS2)C(O)ORS2、-N(RS2)C(O)NRS2 2、-N(RS2)S(O)2RS2、-OP(O)(ORS2)2或-CH2-OP(O)(ORS2),其中各烷基、鹵烷基及烷氧基視情況經一個或兩個-RZ2基團取代;其中各RS2獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代;且各-RZ2獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS3、-SRS3、-NRS3 2、-C(O)RS3、-C(O)ORS3、-C(O)NRS3 2、-S(O)2NRS3 2、-S(O)2RS3、-OC(O)RS3、-N(RS3)C(O)RS3、-OC(O)ORS3、-OC(O)NRS3 2、-N(RS3)C(O)ORS3、-N(RS3)C(O)NRS3 2、-N(RS3)S(O)2RS3、-OP(O)(ORS3)2或-CH2-OP(O)(ORS3);且其中各RS3獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
(2b)Z如(2a)中所描述,其限制條件為Z不為5-(6'-甲基-[2,2'-聯吡啶]-3-基)-1H-吲唑。
(2c)Z如(2a)中所描述,其限制條件為Z不為。
(2d)Z為
式之稠合雙環,其中
環A為Ar或6員Het,環B為5員或6員Het,其中Z視情況經一個或兩個-RZ基團取代,該或該等-RZ基團各自獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS2、-SRS2、-NRS2 2、-C(O)RS2、-C(O)ORS2、-C(O)NRS2 2、-S(O)2NRS2 2、-S(O)2RS2、-OC(O)RS2、-N(RS2)C(O)RS2、-OC(O)ORS2、-OC(O)NRS2 2、-N(RS2)C(O)ORS2、-N(RS2)C(O)NRS2 2、-N(RS2)S(O)2RS2、-OP(O)(ORS2)2或-CH2-OP(O)(ORS2)。
(2e)Z如(2d)中所描述,其限制條件為Z不為5-(6'-甲基-[2,2'-聯吡啶]-3-基)-1H-吲唑。
(2f)Z如(2d)中所描述,其限制條件為Z不為。
(2g)Z為
式之稠合雙環,其中
(1)環A為Ar或6員Het,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;視情況如上文(2a)中所描述經取代。
(2h)Z為
式之稠合雙環,其中
(1)環A為Ar或6員Het,且環B為6員Het;或
(2)環A為6員Het,且環B為5員Het;視情況如上文(2d)中所描述經取代。
(2i)Z為
式之稠合雙環,其中
(1)環A為Ar,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;視情況如上文(2a)中所描述經取代。
(2j)Z為
式之稠合雙環,其中
(1)環A為Ar,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;視情況如上文(2d)中所描述經取代。
(2k)Z為
式之稠合雙環,其中
(1)環A為6員Het,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;視情況如上文(2a)中所描述經取代。
(2l)Z為
式之稠合雙環,其中
(1)環A為6員Het,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;視情況如上文(2d)中所描述經取代。
(2m)Z為
式之稠合雙環,其中
環A為Ar或6員Het,且環B為6員Het;或視情況如上文(2a)中所描述經取代。
(2n)Z為
式之稠合雙環,其中
環A為Ar或6員Het,且環B為6員Het;或視情況如上文(2d)中所描述經取代。
(2o)Z為
式之稠合雙環,其中
環A為Ar,且環B為6員Het;或視情況如上文(2a)中所描述經取代。
(2p)Z為
式之稠合雙環,其中
環A為Ar,且環B為6員Het;或視情況如上文(2d)中所描述經取代。
(2q)Z為
式之稠合雙環,其中
環A為6員Het,且環B為6員Het;或視情況如上文(2a)中所描述經取代。
(2r)Z為
式之稠合雙環,其中
環A為6員Het,且環B為6員Het;或視情況如上文(2d)中所描述經取代。
(2s)Z為
式之稠合雙環,其中
環A為6員Het,且環B為5員Het;視情況如上文(2a)中所描述經取代。
(2t)Z為
式之稠合雙環,其中
環A為6員Het,且環B為5員Het;視情況如上文(2d)中所描述經取代。
(2u)Z為、、、、、
視情況如上文(2a)中所描述經取代。
(2v)Z為、、、、、
視情況如上文(2d)中所描述經取代。
(2w)Z為、、、、或
視情況如上文(2a)中所描述經取代。
(2x)Z為、、、、或
視情況如上文(2d)中所描述經取代。
(2y)Z為、、或;
視情況如上文(2a)中所描述經取代。
(2z)Z為、、或;
視情況如上文(2d)中所描述經取代。
(2aa)Z為或;視情況如上文(2a)中所描述經取代。
(2bb)Z為或;視情況如上文(2d)中所描述經取代。
(2cc)Z為或;視情況如上文(2a)中所描述經取代。
(2dd)Z為或;視情況如上文(2d)中所描述經取代。
(2ee)Z為或;視情況如上文(2a)中所描述經取代。
(2ff)Z為或;視情況如上文(2d)中所描述經取代。
(2gg)Z為或;視情況如上文(2a)中所描述經取代。
(2hh)Z為或;視情況如上文(2d)中所描述經取代。
(2ii)Z為、、、或
視情況如上文(2a)中所描述經取代。
(2jj)Z為、、、或
視情況如上文(2d)中所描述經取代。
(2kk)Z為、或;視情況如上文(2d)中所描述經取代。
(2ll)Z為、或;視情況如上文(2d)中所描述經取代。
(2mm)Z為或;視情況如上文(2d)中所備述經取代。
(2nn)Z為、、或;視情況如上文(2d)中所描述經取代。
(2oo)Z為、或;視情況如上文(2d)中所描述經取代。
(2pp)Z為、、或;視情況如上文(2d)中所描述經取代。
(2qq)Z為、或,
視情況如上文(2a)中所描述經取代,且其中RZ如上文(2a)中所描述。
(2rr)Z為、或,其中RZ如上文(2a)中所描述。
(2ss)Z為、、、、
其中RZ如(2a)中所描述。
(2tt)Z為、、、、
其中RZ如(2d)中所描述。
(2uu)Z為、、、、
其中RZ為-NH2、-氰基或-C(O)NH2。
(2vv)Z為、、、或
其中RZ如(2d)中所描述。
(2ww)Z為、或
其中RZ如(2d)中所描述。
(2xx)Z為或;其中RZ如(2d)中所描述。
(2yy)Z為、、或;其中RZ如(2d)中所描述。
(2zz)Z為或;其中RZ如(2d)中所描述。
(2aaa)Z為或。
(2bbb)Z為、、、、
(2ccc)Z為、、、、
(2ddd)Z為或。
(2eee)Z為、、。
(2fff)Z為或。
(2ggg)Z為。
(2hhh)Z為。
(2iii)Z為。
(2jjj)Z為。
(2kkk)Z為。
(2lll)Z為。
(2mmm)Z為、、、、
視情況如上文(2a)中所描述經取代。
(2nnn)Z為、、、、、
視情況如上文(2d)中所描述經取代。
(2ooo)Z為、、、、、
視情況如上文(2a)中所描述經取代。
(2ppp)Z為、、、、、
視情況如上文(2d)中所描述經取代。
(2qqq)Z為、、、、
視情況如上文(2a)中所描述經取代。
(2rrr)Z為、、、、
視情況如上文(2d)中所描述經取代。
(2sss)Z為、、或;
視情況如上文(2a)中所描述經取代。
(2ttt)Z為、、或;
視情況如上文(2d)中所描述經取代。
(2uuu)Z為、;或
視情況如上文(2a)中所描述經取代。
(2vvv)Z為、;或
視情況如上文(2d)中所描述經取代。
(2www)Z為、、、、
視情況如上文(2a)中所描述經取代。
(2xxx)Z為、、、、
視情況如上文(2d)中所描述經取代。
(2yyy)Z為、、、或
視情況如上文(2d)中所描述經取代。
(2zzz)Z為、、、或
視情況如上文(2d)中所描述經取代。
(2aaaa)Z為、、、、
其中RZ如(2a)中所描述。
(2bbbb)Z為、、、、
其中RZ如(2d)中所描述。
(2cccc)Z為、、、或
其中RZ如(2d)中所描述。
(2dddd)Z為、、、或
其中RZ如(2d)中所描述。
(3a)n為0、1、2、3或4。
(3b)n為0、1、2或3。
(3c)n為0、1或2。
(3d)n為0或1。
(3e)n為0。
(3f)n為1。
(3g)n為2。
(3h)n為3。
(3i)n為4。
本發明之此態樣的特定實施例包含式(I)、式(I')及式(Ia)至式(Im)中之任一者的化合物,其各自如在以下列中之每一者中所定義(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物),其中各項為如上文所定義之群編號(例如,(3i)係指n為4,且短劃「-」指示該變數如在實施例I1中所定義或根據可適用變數定義(1a)-(3i)中之任一者所定義[例如,當R1為短劃時,其可如在實施例I1-I8中之任一者或定義(1a)-(1tt)中之任一者中所定義]:
在一些實施例中,式(I)、式(Ia)至式(Im)、式(II)或式(IIa)至式(IIl)之化合物為以下化合物中之一者(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物):
在此態樣之實施例II1中,本發明包含具有式(II)之結構的化合物:
或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物,其中R1為氫、鹵素、氰基、硝基、C1-6烷基或C1-6鹵烷基;Z為
式之稠合雙環,其中
環A為Ar或6員Het,環B為5員或6員Het,其中Z視情況經一個或兩個-RZ基團取代,該或該等-RZ基團各自獨立地為鹵素、氰基、C1-6烷基、C1-6鹵烷基、-C1-C6烷氧基、-ORS2、-SRS2、-NRS2 2、-C(O)RS2、-C(O)ORS2、-C(O)NRS2 2、-S(O)2NRS2 2、-S(O)2RS2、-OC(O)RS2、-N(RS2)C(O)RS2、-OC(O)ORS2、-OC(O)NRS2 2、-N(RS2)C(O)ORS2、-N(RS2)C(O)NRS2 2、-N(RS2)S(O)2RS2、-OP(O)(ORS2)2或-CH2-OP(O)(ORS2);其中各RS2獨立地為氫、C1-C6烷基、C1-C6鹵烷基、-(C0-C6烷基)-Ar、-(C0-C6烷基)-Het、-(C0-C6烷基)-Cak或-(C0-C6烷基)-Hca,其中Ar、Het、Cak、Hca、烷基及鹵烷基視情況經C1-C6烷基、鹵素、C1-C6鹵烷基或氰基取代。
在實施例II2中,該等化合物為實施例II1之化合物,其限制條件為該化合物不為5-(6'-甲基-[2,2'-聯吡啶]-3-基)-1H-吲唑。
在實施例II3中,該等化合物為實施例II1之化合物,其中Z為
式之稠合雙環,其中
(1)環A為Ar或6員Het,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;其中Z視情況經一個或兩個-RZ基團取代。
在實施例II4中,該等化合物為實施例II1之化合物,其中Z為
其中Z視情況經一個或兩個-RZ基團取代。
在實施例II5中,該等化合物為實施例II1之化合物,其中Z為
其中Z視情況經一個或兩個-RZ基團取代。
在實施例II6中,該等化合物為實施例II1之化合物,其中Z為
其中Z視情況經一個或兩個-RZ基團取代。
在實施例II7中,該等化合物為實施例II1-II6中任一者之化合物,其中Z未經取代。
在實施例II8中,該等化合物為實施例II1-II7中任一者之化合物,其中R1為氫或甲基。
在實施例II9中,本發明化合物為式(IIa)至式(IIl)中之一者,其中R1及Z如在上文實施例II1-II8中所定義:
本發明之此態樣的特定實施例包含式(II)及式(IIa)至式(IIg)中之任一者的化合物,其各自如在以下列中之每一者中所定義(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物),其中各項為如上文所定義之群編號(例如,(1ss)係指R1為甲基,且短劃「-」指示該變數如在實施例I1中所定義或根據可適用變數定義(1a)-(1tt)及(2a)-(2dddd)中之任一者所定義[例如,當R1為短劃時,其可如在實
施例II1-II8中之任一者或可適用定義(1a)-(1tt)中之任一者中所定義]:
在一些實施例中,式(II)或式(IIa)至式(IIg)之化合物為以下化合物中之一者(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物):2、2A、3、4、5、6、9、11、11A、12及12A。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物2(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物2A(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物3(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物4
(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物5(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物6(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物9(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物11(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物11A(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物12(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在其他實施例中,式(II)或式(IIa)至式(IIg)之化合物為化合物12A(或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物)。
在另一態樣中,本發明包含醫藥組合物,其包含根據本發明之前述態樣中之任一者或其任一實施例的化合物與醫藥學上可接受之賦形劑、稀釋劑或載劑一起。
在另一態樣中,本發明包含本發明之前述態樣中之任一者或其任一實施例所描述之化合物的用途,其用於製備用於治療受益於細胞激素信號傳導抑制之醫學疾病或病狀的藥劑。此態樣中所涵蓋之醫學病狀包括本文所描述之所有疾病及病狀。
上文所描述的式(I°)、式(I)、式(I')、式(Ia)至(Im)、式(II)及式(IIa)至式(IIl)之化合物適用作激酶抑制劑及/或細胞激素信號傳導抑制劑。受本發明所揭示之化合物抑制的例示性激酶包括(但不限於)ACVR1;ACVR1B(ALK-4);ACVR1C;ACVR2A;ACVR2B;ACVRL1;BMPR1A;BMPR1B;BMPR2;TGFBR1(ALK-5)、PI3K及MAP4K4(HGK)。其信號傳導受本發明化合物抑制之例示性細胞激素包括(但不限於)TGF-β超級家族,包括活化素、結節素(Nodal)、TGF-β1及GDF-8。在一個態樣中,本發明化合物對一或多種激酶及/或細胞激素信號傳導路徑具有選擇性。舉例而言,例示性化合物抑制TGF-β1信號傳導、GDF-8信號傳導或兩者。在一個態樣中,本發明化合物相對於TGF-β1信號傳導優先抑制GDF-8信號傳導,使得GDF8信號傳導所受之抑制為至少約1.5倍強或為約1.1倍至約25倍強。在一個實施例中,某些化合物抑制GDF8信號傳導達到至少約5倍強,諸如約8倍至約50倍或至少約10倍強,諸如約15倍至約300倍強。
特定言之本發明化合物可用於治療病症,諸如肺高血壓、慢性腎病、急性腎病、傷口癒合、關節炎、骨質疏鬆、腎臟疾病、充血性心臟衰竭、潰瘍、眼部病症、角膜傷口、、糖尿病性腎病變、神經功能損傷、阿茲海默氏病(Alzheimer's disease)、動脈粥樣硬化、腹膜及皮下黏附、腎臟纖維化、肺纖維化(包括特發性肺部纖維化)及肝纖維化、B型肝炎、C型肝炎、酒精誘發之肝炎、癌症、血色病、原發性膽汁性肝硬化、再狹窄、腹膜後纖維化、腸系膜纖維化、子宮內膜異位、瘢痕瘤、癌症、骨骼功能異常、發炎性病症、皮膚結疤及光老
化。
可用本發明化合物治療之特定增生性疾病包括選自以下之彼等疾病:良性或惡性腫瘤、腦癌、腎癌、肝癌、腎上腺癌、膀胱癌、乳房癌、胃癌、胃腫瘤、卵巢癌、結腸癌、直腸癌、前列腺癌、胰臟癌、肺癌、陰道癌或甲狀腺癌、肉瘤、神經膠母細胞瘤、多發性骨髓瘤或胃腸癌(尤其結腸癌或結腸直腸腺瘤)或頸部及頭部之腫瘤、表皮過度增生、黑素瘤、牛皮癬、前列腺增生、贅瘤、上皮細胞特徵之贅瘤、白血病及淋巴瘤、乳癌或白血病。
本文所描述之化合物亦包括同位素標記之化合物,其中一或多個原子之原子質量與習知地見於自然界中之原子質量不同。可併入本文所揭示之化合物中的同位素之實例包括(但不限於)2H、3H、11C、13C、14C、15N、18O、17O、18F等。因此,相對於此類同位素之天然豐度,所揭示之化合物可富含此等同位素中之一或多者。如熟習此項技術者已知的,此類經同位素增濃之化合物適用於多種目的。舉例而言,用較重同位素(諸如氘(2H))取代可得到由更大代謝穩定性所產生之某些治療優勢。用正電子發射同位素(諸如18F)取代可適用於正電子發射斷層攝影術(PET)研究。藉助於實例,氘(2H)之天然豐度約為0.015%。因此,大致每6,500個存在於自然界中之氫原子中存在一個氘原子。本文具體涵蓋在一或多個位置富含氘之化合物。因此,本發明之含氘化合物以大於0.015%之豐度在一或多個位置處(視具體情況而定)具有氘。
在另一態樣中,本發明包含用於治療癌症之組合療法,該癌症包括前惡性及惡性贅瘤兩者。在此態樣中,本發明包含一種治療癌症之方法,其包含由本文所揭示之化合物與治療性癌症處理法組合投與個體。在本發明之一些實施例中,本文所揭示之化合物與癌症之標準照護抗增生治療法組合使用。本文所揭示之化合物用於組合療法中的
量為足以抑制TGF-β超級家族成員(諸如結節素及活化素,其促進癌症幹細胞之存活及/或分化)的量,且從而增強治療性處理法之功效。被標準照護治療法破壞之腫瘤將可藉由本發明化合物治療而阻斷癌症幹細胞再生的能力。治療功效可藉由一般用於所治療之特定癌症的任何技術公認之方法來測定,且包括例如腫瘤生長之延遲、抑制或消退。
提及「組合療法」及使用本文所揭示之化合物與另一種治療性處理法「結合」治療意謂該化合物及另一種治療性處理法可同時或依序投與,以使得所得治療比單獨任一治療更有效。
在個體中治療癌症之一個實施例包含由上文所描述用量的本文所揭示化合物與治療有效量之一或多種化學治療劑組合投與有需要之個體,其中該一或多種化學治療劑係選自由以下各者組成之群:抗代謝物、烷基化劑、配位化合物、鉑複合物、DNA交聯化合物、轉錄酶抑制劑、酪胺酸激酶抑制劑、蛋白質激酶抑制劑、拓撲異構酶抑制劑、DNA小溝結合化合物、長春花生物鹼、紫杉烷、抗腫瘤抗生素、激素、芳香酶抑制劑、酵素、生長因子受體抗體、細胞激素、細胞表面標記物抗體、HDAC抑制劑、HSP 90抑制劑、BCL-2抑制劑、B-raf抑制劑、MEK抑制劑、mTOR抑制劑、蛋白酶體抑制劑及單株抗體。
適用於本發明中之BCL-2抑制劑中之一為ABT-199。
用於治療個體之方法的另一個實施例包含由(如上文所描述)的一定量本文所揭示化合物與治療有效量之一或多種化學治療劑組合投與該個體,該一或多個種化學治療劑獨立地選自由以下各者組成之群:氮芥(mechlorothamine)、環磷醯胺、異環磷醯胺(ifosfamide)、美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、伸乙亞胺(ethyleneimines)、甲基三聚氰胺、丙卡巴肼(procarbazine)、達卡巴嗪(dacarbazine)、替莫唑胺(temozolomide)、白消安(busulfan)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、甲胺喋呤(methotrexate)、氟尿嘧啶
(fluorouracil)、卡培他濱(capecitabine)、阿糖胞苷(cytarabine)、吉西他濱(gemcitabine)、胞嘧啶阿拉伯糖苷(cytosine arabinoside)、巰基嘌呤、氟達拉濱(fludarabine)、克拉屈濱(cladribine)、硫鳥嘌呤、硫唑嘌呤(azathioprine)、長春鹼(vinblastine)、長春新鹼(vincristine)、太平洋紫杉醇(paclitaxel)、多西他賽(docetaxel)、秋水仙鹼(colchicine)、放線菌素D(actinomycin D)、道諾黴素(daunorubicin)、博萊黴素(bleomycin)、L-天冬醯胺酶、順鉑(cisplatin)、卡鉑(carboplatin)、奧沙利鉑(oxaliplatin)、潑尼松(prednisone)、地塞米松(dexamethasone)、胺基格魯米特(amino glutethimide)、福美司坦(formestane)、阿那曲唑(anastrozole)、己酸羥基孕酮(hydroxyprogesterone caproate)、甲羥孕酮(medroxyprogesterone)、他莫昔芬(tamoxifen)、安吖啶(amsacrine)、米托蒽醌(mitoxantrone)、拓朴替康(topotecan)、伊立替康(irinotecan)、喜樹鹼(camptothecin)、阿法替尼(afatinib)、阿西替尼(axitinib)、伯舒替尼(bosutinib)、硼替佐米(bortezomib)、卡非佐米(carfilzomib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、克卓替尼(crizotinib)、達沙替尼(dasatinib)、達拉菲尼(dabrafenib)、依維莫司(evorolimus)、依魯替尼(ibrutinib)、LDK378、LGX818、MEK162、瑞戈非尼(regorafenib)、蘆可替尼(ruxolitinib)、司美替尼(selumetinib)、索拉非尼(sorafenib)、曲美替尼(trametinib)、維羅非尼(vemurafenib)、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、伊馬替尼(imatinib)、拉帕替尼(lapatinib)、來他替尼(lestaurtinib)、尼羅替尼(nilotinib)、帕博西里(palbociclib)、帕佐泮尼(pazopanib)、帕瑪替尼(pomatinib)、司馬沙尼(semaxanib)、西羅莫司(sirolimus)、舒尼替尼(sunitinib)、坦羅莫司(temsirolimus)、凡塔藍尼(vatalanib)、凡德他尼(vandetanib)、抗Her2抗體、干擾素-α、干擾素-γ、介白素2、GM CSF、抗CTLA 4抗體、利妥昔單抗(rituximab)、抗
CD33抗體、MGCD0103、伏立諾他(vorinostat)、17-AAG、沙立度胺(thalidomide)、來那度胺(lenalidomide)、雷帕黴素(rapamycin)、CCI-779、小紅莓(doxorubicine)、吉西他濱(gemcitabine)、美法侖(melphalan)、NPI052、吉妥單抗(gemtuzumab)、阿侖單抗(alemtuzumab)、西妥昔單抗(cetuximab)、替伊莫單抗提烏克斯坦(ibritumomab tiuxaetan)、托西莫單抗(tositumomab)、碘-131托西莫單抗、曲妥珠單抗(trastuzumab)、阿多-曲妥珠單抗恩他新(ado-trastuzumab emtansine)、歐比托珠單抗(obinutuzumab)、貝伐單抗(bevacizumab)、利妥昔單抗(rituximab)及抗TRAIL死亡受體抗體。
在可用於本發明中之CTLA 4抗體當中為伊派利單抗(ipilimumab),其由Bristol-Myers Squibb作為YERVOY®出售。
其他化學治療劑包括檢查點路徑抑制劑,例如PD-1抑制劑,諸如尼沃單抗(nivolumab)及拉立珠單抗(lambrolizumab);及PD-L1抑制劑,諸如派立珠單抗、MEDI-4736及MPDL3280A/RG7446。用於與本文所揭示之化合物組合的另外之檢查點抑制劑包括抗LAG-3劑,諸如BMS-986016(MDX-1408)。
用於與本發明所揭示之TGF-β信號傳導抑制劑組合的其他化學治療劑包括抗SLAMF7劑,諸如人類化單株抗體埃羅妥珠單抗(elotuzumab)(BMS-901608);抗KIR劑,諸如抗KIR單株抗體利瑞路單抗(lirilumab)(BMS-986015);及抗CD137劑,諸如完全人類單株抗體優瑞路單抗(urelumab)(BMS-663513)。
下表顯示在本發明之組合療法及與本文所揭示之化合物一起使用的治療藥物及/或其他治療中可治療的例示性癌症:
在另一態樣中,本發明包含一種測定及量測本文所揭示之化合物抑制TGF-β超級家族成員(諸如結節素(Nodal)及活化素(Activin))信號傳導之能力的方法,以便鑑別癌症及更確切而言,腫瘤。在一個實施例中,對此類組合療法敏感之贅瘤可藉由使用熟習此項技術者已知之技術測試結節素及活化素信號傳導活性來鑑別,該等技術包括例如Lonardo,E.等人(2011)Cell Stem Cell 9,433-446(其以全文引用之方式併入本文中)中所描述之分析。視情況在此實施例中,如本文所描述,在發現所測試之化合物在所測試之贅瘤中抑制TGF-β超級家族成員(諸如結節素及活化素)之信號傳導的情況下,該化合物隨後用於治療該贅瘤之組合療法中。
本文所用之術語可前加及/或後接單短劃「-」或雙短劃「=」以指示所命名之取代基與其母基團之間的鍵之鍵順序;單短劃指示單鍵,且雙短劃指示雙鍵或在螺-取代基的情況下指示一對單鍵。在不存在單短劃或雙短劃的情況下。應理解單鍵形成於取代基與其母基團之間;此外,除非短劃另外指示,否則意欲「左向右」讀取取代基。舉例而言,芳基烷基、芳基烷基-及-烷基芳基指示相同官能基。
為簡單起見,定義化學部分,且在通篇中主要作為單價化學部分(例如烷基、芳基等)提及。儘管如此,此類術語亦用於在熟習此項
技術者清楚之適當結構情況下傳達相應多價部分。舉例而言,雖然「烷基」部分可指單價基團(例如CH3-CH2-),但在某些情況下,二價連接部分可為「烷基」,在此情況下熟習此項技術者將理解,該等烷基為二價基團(例如-CH2-CH2-),其等效於術語「伸烷基」。(類似地,在其中需要二價部分且將其陳述為「芳基」的情況下,熟習此項技術者應理解,術語「芳基」係指相應二價部分,伸芳基)。理解所有原子具有其一般用於鍵形成之價數(亦即,對碳為4,對N為3,對O為2,且視S之氧化態而定,對S為2、4或6)。本發明所揭示之化合物中的氮可為超價的,例如N-氧化物或四取代銨鹽。部分偶爾可定義為例如(A)a-B-,其中a為0或1。在此等情況下,當a為0時,該部分為B-,且當a為1時,該部分為A-B-。
如本文所用,術語「烷基」包括具有經設計之數目個碳原子,諸如1至6個碳(亦即,包括1及6)、1至6個碳、1至3個碳、或1、2、3、4、5或6個碳的烷基、烯基及炔基。術語「Cm-Cn烷基」意謂具有m至n個碳原子(亦即,包括m及n)之烷基)。術語「Cm-Cn烷基」意謂具有m至n個碳原子之烷基。舉例而言,「C1-C6烷基」為具有一至六個碳原子之烷基。烷基(alkyl/alkyl group)可為直鏈或分支鏈的,且視情形而定,可為單價基團或二價基團(亦即伸烷基)。在具有零個碳原子之烷基(亦即「C0烷基」)的情況下,若該基團為二價基團,則其簡單地為單共價鍵,或若其為單價基團,則為氫原子。舉例而言,部分「-(C0-C6烷基)-Ar」表示視情況經取代之芳基經由單鍵或具有1至6個碳之伸烷基橋連接。「烷基」之實例包括例如甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基及第三丁基、戊基、己基、庚基、3-乙基丁基、3-己烯基及炔丙基。若未指定碳原子數目,則標的「烷基」或「烷基」部分具有1至6個碳。
術語「鹵烷基」為經一或多個鹵素原子,例如F、Cl、Br及I取代
之烷基。更具體術語,例如「氟烷基」為經一或多個氟原子取代之烷基。「氟烷基」之實例包括氟甲基、二氟甲基、三氟甲基、五氟乙基、六氟異丙基及其類似基團。在本文所揭示之化合物的某些實施例中,各鹵烷基為氟烷基。
術語「芳基」或「Ar」表示具有單個環之芳環系統(例如苯基),其視情況與其他芳族烴環或非芳族烴環稠合。「芳基」包括具有多個稠環且其中至少一個環為碳環及芳環之環系統(例如1,2,3,4-四氫萘基、萘基)。芳基之實例包括苯基、1-萘基、2-萘基、茚滿基(indanyl)、茚基(indenyl)、二氫萘基、茀基(fluorenyl)、萘滿基(tetralinyl)、及6,7,8,9-四氫-5H-苯并[a]環庚烯基。在某些實例中,芳基包括第一碳環、芳環與芳族或脂族雜環稠合之彼等芳基,例如2,3-二氫苯并呋喃基。本文之芳基未經取代,或當指定為「視情況經取代」時,除非另外說明,否則可在一或多個可取代位置中經如下文所描述之各種基團取代。
術語「雜芳基」或「Het」係指在芳環中含有至少一個選自氮、氧及硫之雜原子的芳環系統。雜芳基最常將具有1、2、3或4個雜原子。雜芳基可與一或多個非芳環(例如環烷基或雜環烷基環)稠合,其中該環烷基(Cak)及雜環烷基(Hca)環描述於本文中。在本發明化合物之一個實施例中,雜芳基經由雜芳基芳環中之原子鍵結至結構之其餘部分。在另一個實施例中,雜芳基經由非芳環原子鍵結至結構之其餘部分。雜芳基之實例包括例如吡啶基、嘧啶基、喹啉基、苯并噻吩基、吲哚基、吲哚啉基、噠嗪基、吡嗪基、異吲哚基、異喹啉基、喹唑啉基、喹喔啉基、酞嗪基、咪唑基、異噁唑基、吡唑基、噁唑基、噻唑基吲哚嗪基吲唑基、苯并噻唑基、苯并咪唑基、苯并呋喃基、呋喃基、噻吩基、吡咯基噁二唑基、噻二唑基、苯并[1,4]噁嗪基、三唑基、四唑基、異噻唑基、啶基、異烷基、烷基、四氫異喹啉
基、異吲哚啉基、異苯并四氫呋喃基、異苯并四氫噻吩基、異苯并噻吩基、苯并噁唑基、吡啶并吡啶基、苯并四氫呋喃基、苯并四氫噻吩基、嘌呤基、苯并間二氧雜環戊烯基、三嗪基、喋啶基(pteridinyl)、苯并噻唑基、咪唑并吡啶基、咪唑并噻唑基、二氫苯并異噁嗪基、苯并異噁嗪基、苯并噁嗪基、二氫苯并異噻嗪基、苯并哌喃基、苯并硫哌喃基、色酮基(chromonyl)、色滿酮基(chromanonyl)、吡啶基-N-氧化物、四氫喹啉基、二氫喹啉基、二氫喹啉酮基、二氫異喹啉酮基、二氫香豆素基、二氫異香豆素基、異吲哚啉基、苯并二噁烷基、苯并噁唑酮基(benzoxazolinonyl)、吡咯基N-氧化物、嘧啶基N-氧化物、噠嗪基N-氧化物、吡嗪基N-氧化物、喹啉基N-氧化物、吲哚基N-氧化物、吲哚啉基N-氧化物、異喹啉基N-氧化物、喹唑啉基N-氧化物、喹喏啉基N-氧化物、酞嗪基N-氧化物、咪唑基N-氧化物、異噁唑基N-氧化物、噁唑基N-氧化物、噻唑基N-氧化物、吲哚嗪基N-氧化物、吲唑基N-氧化物、苯并噻唑基N-氧化物、苯并咪唑基N-氧化物、吡咯基N-氧化物、噁二唑基N-氧化物、噻二唑基N-氧化物、三唑基N-氧化物、四唑基N-氧化物、苯并硫哌喃基S-氧化物苯并硫哌喃基S,S-二氧化物。較佳雜芳基包括吡啶基、嘧啶基、喹啉基、吲哚基、吡咯基、呋喃基、噻吩基及咪唑基、吡唑基、吲唑基、噻唑基及苯并噻唑基。在某些實施例中,各雜芳基係選自吡啶基、嘧啶基、噠嗪基、吡嗪基、咪唑基、異噁唑基、吡唑基、噁唑基、噻唑基、呋喃基、噻吩基、吡咯基、噁二唑基、噻二唑基、三唑基、四唑基、異噻唑基、吡啶基-N-氧化物、吡咯基N-氧化物、嘧啶基N-氧化物、噠嗪基N-氧化物、吡嗪基N-氧化物、咪唑基N-氧化物、異噁唑基N-氧化物、噁唑基N-氧化物、噻唑基N-氧化物、吡咯基N-氧化物、噁二唑基N-氧化物、噻二唑基N-氧化物、三唑基N-氧化物及四唑基N-氧化物。較佳雜芳基包括吡啶基、嘧啶基、喹啉基、吲哚基、吡咯基、呋喃基、噻吩基、咪唑
基、吡唑基、吲唑基、噻唑基及苯并噻唑基。本文之雜芳基未經取代,或當指定為「視情況經取代」時,除非另外說明,否則可在一或多個可取代位置中經如下文所描述之各種基團取代。
術語「雜環烷基」或「Hca」係指含有至少一個較佳選自氮、氧及硫之雜原子的非芳環或環系統,其中該雜原子處於非芳環中。雜環烷基可具有1、2、3或4個雜原子。雜環烷基可為飽和的(亦即雜環烷基)或部分不飽和的(亦即雜環烯基)。雜環烷基包括三至八個環原子之單環基團,以及雙環及多環系統,包括橋連及稠合系統,其中各環包括三至八個環原子。雜環烷基環視情況與其他雜環烷基環及/或非芳族烴環及/或苯基環稠合。在某些實施例中,雜環烷基在單個環中具有3至7個成員。在其他實施例中,雜環烷基在單個環中具有5或6個成員。在一些實施例中,雜環烷基在單個環中具有3、4、5、6或7個成員。雜環烷基之實例包括例如氮雜雙環[2.2.2]辛基(在各情況下亦為「啶基」或啶衍生物)、氮雜雙環[3.2.1]辛基、2,5-二氮雜雙環[2.2.1]庚基、嗎啉基、硫代嗎啉基、硫代嗎啉基S-氧化物、硫代嗎啉基S,S-二氧化物、2-噁唑啉酮基(oxazolidonyl)、哌嗪基、高哌嗪基、哌嗪酮基(piperazinonyl)、吡咯啶基、氮雜環庚烷基、氮雜環丁基、吡咯啉基、四氫哌喃基、哌啶基、四氫呋喃基、四氫噻吩基、3,4-二氫異喹啉-2(1H)-基、異吲哚吲哚基(isoindolindionyl)、高哌啶基、高硫嗎啉基、高硫嗎啉基S,S-二氧化物、噁唑啶酮基(oxazolidinonyl)、二氫吡唑基、二氫吡咯基、二氫吡嗪基、二氫吡啶基、二氫嘧啶基、二氫呋喃基、二氫哌喃基、咪唑啉酮基(imidazolidonyl)、四氫噻吩基S-氧化物、四氫噻吩基S,S-二氧化物及高硫嗎啉基S-氧化物。尤其需要之雜環烷基包括嗎啉基、3,4-二氫異喹啉-2(1H)-基、四氫哌喃基、哌啶基、氮雜-雙環[2.2.2]辛基、γ-丁內酯基(亦即經側氧基取代之四氫呋喃基)、γ-丁內醯胺基(亦即經側氧基取代之吡咯啶)、吡咯啶基、
哌嗪基、氮雜環庚烷基、氮雜環丁基、硫代嗎啉基、硫代嗎啉基S,S-二氧化物、2-噁唑啉酮基、咪唑啉酮基、異吲哚吲哚基、哌嗪酮基。本文之雜環烷基未經取代,或當指定為「視情況經取代」時,除非另外說明,否則可在一或多個可取代位置中經如下文所描述之各種基團取代。
術語「環烷基」或「Cak」係指非芳族碳環或環系統,其可為飽和的(亦即環烷基)或部分不飽和的(亦即環烯基)。環烷基環視情況與其他環烷基環稠合或以其他方式附接(例如橋連系統)至其他環烷基環。存在於所揭示之化合物中的環烷基之某些實例在單個環中具有3至7個成員,諸如在單個環中具有5或6個成員。在一些實施例中,環烷基在單個環中具有3、4、5、6或7個成員。環烷基之實例包括,例如環己基、環戊基、環丁基、環丙基、四氫萘基及雙環[2.2.1]庚烷。本文之環烷基未經取代,或當指定為「視情況經取代」時,可在一或多個可取代位置中經各種基團取代。
術語「環系統」涵蓋單環以及稠合及/或橋連多環。
術語「氧雜」意謂鏈中之二價氧基團,有時標識為-O-。
術語「側氧基」意謂雙鍵結合之氧,有時標識為=O,或例如在描述羰基中,「C(O)」可用於展示經側氧基取代之碳。
術語「拉電子基團」意謂與類似地附接之氫原子相比將電子密度拉離其所附接之結構的基團。舉例而言,拉電子基團可選自由以下各者組成之群:鹵基(例如氟、氯、溴及碘)、氰基、-(C1-C4氟烷基)、-O-(C1-C4氟烷基)、-C(O)-(C0-C4烷基)、-C(O)O-(C0-C4烷基)、-C(O)N(C0-C4烷基)(C0-C4烷基)、-S(O)2O-(C0-C4烷基)、NO2及-C(O)-Hca(其中Hca包括結合-C(O)-之氮原子),其中無烷基、氟烷基或雜環烷基經含芳基、雜芳基、環烷基或雜環烷基之基團取代。
術語「經取代」在用於修飾指定基(group)或基團(radical)時意
謂,除非另外規定,否則該指定基或基團之一或多個氫原子彼此獨立地各自經如下文所定義之相同或不同取代基置換。
除非另外說明,否則用於取代指定基或基團中飽和碳原子上之氫的取代基為-R60、鹵基、-O-M+、=O、-OR70、-SR70、-S-M+、=S、-NR80R80、=NR70、=N-OR70、三鹵甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-SO2R70、-SO2O-M+、-SO2OR70、-OSO2R70、-OSO2O-M+、-OSO2OR70、-P(O)(O-)2(M+)2、-P(O)(OR70)O-M+、-P(O)(OR70)2、-C(O)R70、-C(S)R70、-C(NR70)R70、-C(O)O-M+、-C(O)OR70、-C(S)OR70、-C(O)NR80R80、-C(NR70)NR80R80、-OC(O)R70、-OC(S)R70、-OC(O)O-M+、-OC(O)OR70、-OC(S)OR70、-NR70C(O)R70、-NR70C(S)R70、-NR70CO2 -M+、-NR70CO2R70、-NR70C(S)OR70、-NR70C(O)NR80R80、-NR70C(NR70)R70及-NR70C(NR70)NR80R80。各R60獨立地選自由以下各者組成之群:烷基、雜烷基、環烷基、雜環烷基、雜環烷基烷基、環烷基烷基、芳基、芳基烷基、雜芳基及雜芳基烷基,其中之每一者視情況經1、2、3、4或5個選自由以下各者組成之群的基團取代:鹵基、-O-M+、=O、-OR71、-SR71、-S-M+、=S、-NR81R81、=NR71、=N-OR71、三鹵甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-SO2R71、-SO2O-M+、-SO2OR71、-OSO2R71、-OSO2O-M+、-OSO2OR71、-P(O)(O-)2(M+)2、-P(O)(OR71)O-M+、-P(O)(OR71)2、-C(O)R71、-C(S)R71、-C(NR71)R71、-C(O)O-M+、-C(O)OR71、-C(S)OR71、-C(O)NR81R81、-C(NR71)NR81R81、-OC(O)R71、-OC(S)R71、-OC(O)O-M+、-OC(O)OR71、-OC(S)OR71、-NR71C(O)R71、-NR71C(S)R71、-NR71CO2 -M+、-NR71CO2R71、-NR71C(S)OR71、-NR71C(O)NR81R81、-NR71C(NR71)R71及-NR71C(NR71)NR81R81。各R70獨立地為氫或R60;各R80獨立地為R70或替代性地,兩個R80與其所鍵結之氮原子結合在一起形成5員、6員
或7員雜環烷基,其可視情況包括1至4個相同或不同的選自由O、N及S組成之群的另外之雜原子,其中N可具有-H或C1-C3烷基取代;且各M+為具有淨單正電荷之相對離子。各R71獨立地為氫或R61,其中R61為烷基、雜烷基、環烷基、雜環烷基、雜環烷基烷基、環烷基烷基、芳基、芳基烷基、雜芳基及雜芳基烷基,其中之每一者視情況經1、2、3、4或5個選自由以下各者組成之群的基團取代:鹵基、-O-M+、=O、-OR72、-SR72、-S-M+、=S、-NR82R82、=NR72、=N-OR72、三鹵甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-SO2R71、-SO2O-M+、-SO2OR72、-OSO2R72、-OSO2O-M+、-OSO2OR72、-P(O)(O-)2(M+)2、-P(O)(OR72)O-M+、-P(O)(OR72)2、-C(O)R72、-C(S)R72、-C(NR72)R72、-C(O)O-M+、-C(O)OR72、-C(S)OR72、-C(O)NR82R82、-C(NR72)NR82R82、-OC(O)R72、-OC(S)R72、-OC(O)O-M+、-OC(O)OR72、-OC(S)OR72、-NR72C(O)R72、-NR72C(S)R72、-NR72CO2 -M+、-NR72CO2R72、-NR72C(S)OR72、-NR72C(O)NR82R82、-NR72C(NR72)R72及-NR72C(NR72)NR82R82;且各R81獨立地為R71或替代性地,兩個R81與其所鍵結之氮原子結合在一起形成5員、6員或7員雜環烷基,其可視情況包括1至4個相同或不同的選自由O、N及S組成之群的另外之雜原子,其中N可具有-H或C1-C3烷基取代。各R72獨立地為氫、(C1-C6烷基)或(C1-C6氟烷基);各R82獨立地為R72或替代性地,兩個R82與其所鍵結之氮原子結合在一起形成5員、6員或7員雜環烷基,其可視情況包括1、2、3或4個相同或不同的選自由O、N及S組成之群的另外之雜原子,其中N可具有-H或C1-C3烷基取代。各M+可獨立地為例如鹼金屬離子,諸如K+、Na+、Li+;銨離子,諸如+N(R60)4;或鹼土金屬離子,諸如[Ca2+]0.5、[Mg2+]0.5或[Ba2+]0.5(「下標0.5意謂例如,此類二價鹼土離子之相對離子中之一者可為本發明所揭示之化合物的離子化形式,且另一者為典型相對離
子(諸如氯離子),或兩個離子化的本發明所揭示之分子可充當此類二價鹼土離子之相對離子,或雙重離子化之化合物可充當此類二價鹼土離子之相對離子)。作為具體實例,-NR80R80意謂包括-NH2、-NH-烷基、N-吡咯啶基、N-哌嗪基、4-甲基-哌嗪-1-基及N-嗎啉基。
除非另外說明,否則用於「經取代之」烯烴、炔烴、芳基及雜芳基中不飽和碳原子上之氫的取代基為-R60、鹵基、-O-M+、-OR70、-SR70、-S-M+、-NR80R80、三鹵甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、-N3、-SO2R70、-SO3 -M+、-SO3R70、-OSO2R70、-OSO3 -M+、-OSO3R70、-PO3 -2(M+)2、-P(O)(OR70)O-M+、-P(O)(OR70)2、-C(O)R70、-C(S)R70、-C(NR70)R70、-CO2 -M+、-CO2R70、-C(S)OR70、、C(O)NR80R80、-C(NR70)NR80R80、-OC(O)R70、-OC(S)R70、-OCO2 -M+、-OCO2R70、-OC(S)OR70、-NR70C(O)R70、-NR70C(S)R70、-NR70CO2 -M+、-NR70CO2R70、-NR70C(S)OR70、-NR70C(O)NR80R80、-NR70C(NR70)R70及-NR70C(NR70)NR80R80,其中R60、R70、R80及M+如先前所定義。
除非另外說明,否則用於「經取代之」雜烷基及雜環烷基中氮原子上之氫的取代基為-R60、-O-M+、-OR70、-SR70、-S-M+、-NR80R80、三鹵甲基、-CF3、-CN、-NO、-NO2、-S(O)2R70、-S(O)2O-M+、-S(O)2OR70、-OS(O)2R70、-OS(O)2O-M+、-OS(O)2OR70、-P(O)(O-)2(M+)2、-P(O)(OR70)O-M+、-P(O)(OR70)(OR70)、-C(O)R70、-C(S)R70、-C(NR70)R70、-C(O)OR70、-C(S)OR70、-C(O)NR80R80、-C(NR70)NR80R80、-OC(O)-R70、-OC(S)R70、-OC(O)OR70、-OC(S)OR70、-NR70C(O)R70、-NR70C(S)R70、-NR70C(O)OR70、-NR70C(S)OR70、-NR70C(O)NR80R80、-NR70C(NR70)R70及-NR70C(NR70)NR80R80,其中R60、R70、R80及M+如先前所定義。
在本文所揭示之化合物的某些實施例中,經取代之之基團具有1、2、3或4個取代基,1、2或3個取代基,1或2個取代基,或1個取代
基。
在某些實施例中,「經取代之」烷基、環烷基、雜環烷基、芳基及雜芳基上的取代基為-鹵基、-OH、-O-(C1-C4烷基)、-O-(C1-C4鹵烷基)、-N(C0-C4烷基)(C0-C4烷基)、-SH、-S(O)0-2-(C1-C4烷基)、-(C1-C4烷基)、-(C1-C4鹵烷基)、-C(O)-(C0-C4烷基)、-C(O)N(C0-C4烷基)(C0-C4烷基)、-N(C0-C4烷基)C(O)(C0-C4烷基)(C0-C4烷基)、-C(O)O-(C0-C4烷基)、-OC(O)-(C0-C4烷基)、S(O)2-O(C0-C4烷基)及-NO2,其中無烷基進一步經取代。
本文所揭示之化合物亦可以醫藥學上可接受之鹽的形式提供。術語「醫藥學上可接受之鹽」或「其醫藥學上可接受之鹽」係指由醫藥學上可接受之無毒酸或鹼(包括無機酸及無機鹼及有機酸及有機鹼)製備的鹽。若化合物為鹼性,則鹽可由醫藥學上可接受之無毒酸製備。此類鹽可為例如以下酸中之至少一者的酸加成鹽:苯磺酸、檸檬酸、α-葡糖庚酸、D-葡萄糖酸、乙醇酸、乳酸、蘋果酸、丙二酸、杏仁酸、磷酸、丙酸、丁二酸、硫酸、酒石酸(d、l或dl)、對甲苯磺酸(甲苯磺酸)、戊酸、棕櫚酸、雙羥萘酸、癸二酸、硬脂酸、月桂酸、乙酸、己二酸、碳酸、4-氯苯磺酸、乙二磺酸、乙基丁二酸、反丁烯二酸、半乳糖二酸(黏液酸)、D-葡糖醛酸、2-側氧基-戊二酸、甘油磷酸、馬尿酸、羥乙基磺酸(乙醇磺酸)、乳糖酸、順丁烯二酸、1,5-萘-二磺酸、2-萘-磺酸、特戊酸、對苯二甲酸、硫氰酸、膽酸、硫酸正十二烷酯、3-羥基-2-萘甲酸、1-羥基-2-萘甲酸、油酸、十一碳烯酸、抗壞血酸、(+)-樟腦酸、d-樟腦磺酸、二氯乙酸、乙磺酸、甲酸、氫碘酸、氫溴酸、鹽酸、甲磺酸、菸鹼酸、硝酸、乳清酸、乙二酸、苦味酸、L-焦麩胺酸、糖精、柳酸、龍膽酸及/或4-乙醯胺基苯甲酸。
本文所描述之化合物亦可以前藥形式提供。「前藥」係指活性化
合物(藥物)之衍生物,其在使用條件下(諸如在身體內)進行轉換以釋放活性藥物。前藥經常但不一定為藥理學上非活性的,直至轉化為活性藥物為止。前藥通常藉由用前基團(下文定義)掩蔽藥物中咸信為活性部分所需之官能基以形成前部分來獲得,該前部分在指定使用條件下進行轉換(諸如裂解)以釋放官能基且因此釋放活性藥物。前部分之裂解可自發地進行,諸如藉助於水解反應;或其可由另一種試劑催化或誘導,諸如藉由酶,藉由光、藉由酸、或藉由物理或環境參數變化或暴露於其中(諸如溫度之變化)。試劑對於使用條件可為內源性的,諸如存在於前藥所投與之細胞中的酶或胃之酸性條件,或其可外源性地進行供應。適合於在活性藥物中掩蔽官能基以產生前藥的多種前基團以及所得前部分為此項技術中熟知的。舉例而言,羥基官能基可掩蔽為磺酸酯、酯或碳酸酯前部分,其可活體內水解以提供該羥基。胺基官能基可掩蔽為醯胺、胺基甲酸酯、亞胺、脲、苯膦基、磷醯基或次磺醯基前部分,其可活體內水解以提供該胺基。羧基可掩蔽為酯(包括矽烷基酯及硫酯)、醯胺或醯肼前部分,其可活體內水解以提供該羧基。適合之前基團及其相應前部分的具體實例對熟習此項技術者將為顯而易見的。
本文所揭示之化合物亦可以N-氧化物形式提供。
本發明所揭示之化合物、鹽、前藥及N-氧化物可例如以溶劑合物或水合物形式提供。
一般熟習醫藥化學技術者亦將瞭解,所揭示之結構意欲包括本發明化合物的經同位素增濃之形式。如本文所用,「同位素」包括具有相同原子數但不同質量數之彼等原子。如熟習此項技術者已知的,某些原子(諸如氫)以不同同位素形式存在。舉例而言,氫包括三種同位素形式,氕、氘及氚。如在考慮本發明化合物後對於熟習此項技術者將為顯而易見的,某些化合物可在既定位置處由該位置處原子之特
定同位素增濃。舉例而言,具有氟原子之化合物可合成為富含放射性氟同位素18F之形式。類似地,化合物可富含氫之重同位素:氘及氚;且類似地,可富含碳之放射性同位素,諸如13C。此類同位素變異化合物經歷不同代謝路徑,且可適用於例如研究一或多種激酶及/或細胞激素信號傳導路徑及其在疾病中之作用。
如本文所用,術語「細胞」意謂指活體外、離體或活體內之細胞。在一些實施例中,離體細胞可為自有機體(諸如哺乳動物)切除之組織樣本的一部分。在一些實施例中,活體外細胞可為細胞培養物中之細胞。在一些實施例中,活體內細胞為存活於有機體(諸如哺乳動物)中之細胞。
如本文所用,術語「接觸」係指將所指示部分彙集於活體外系統或活體內系統中。舉例而言,使酶與化合物「接觸」包括向個體或患者(諸如人類)投與本文所描述之化合物,以及例如將化合物引入至含有含酶之細胞製劑或純化製劑中的樣本中。
如本文所用,術語「個體(individual)」、「患者」或「個體(subject)」可互換使用,係指任何動物,包括哺乳動物,較佳為小鼠、大鼠、其他嚙齒動物、兔、大、貓、豬、牛、羊、馬或靈長類動物,且最佳為人類。
如本文所用,短語「治療有效量」係指在組織、系統、動物、個體或人類中引起研究人員、獸醫、醫生或其他臨床醫師所尋求之生物或藥物反應的活性化合物或醫藥劑之量。
在某些實施例中,治療有效量可為適合於以下各者之量:(1)預防疾病;舉例而言,在可能傾向於患有或以其他方式易患疾病、病狀或病症但尚未經歷或顯示該疾病之病理學或症候學的個體中預防該疾病、病狀或病症;(2)抑制疾病;舉例而言,在經歷或顯示疾病、病狀或病症之
病理學或症候學的個體中抑制該疾病、病狀或病症;或(3)改善疾病(包括其症狀);舉例而言,在經歷或顯示疾病、病狀或病症之病理學或症候學的個體中改善該疾病、病狀或病症(亦即,使病理學及/或症候學反轉),諸如降低疾病嚴重性。
如此處所用,術語「治療(treatment/treating)」意謂(i)改善所提及之疾病病況、病狀或病症(或其症狀),諸如在經歷或顯示疾病、病狀或病症之病理學或症候學的個體中改善該疾病、病狀或病症(亦即,使病理學及/或症候學反轉或改良),諸如降低疾病或其症狀之嚴重性;或(ii)引發所提及之生物學作用(例如GDF-8或TGF-β1之調節或抑制)。
藉由抑制GDF-8或TGF-β1來改善疾病病狀的操作可能需要同時或依序投與另外之治療劑,諸如在癌症之情況下投與抗腫瘤劑或在病毒性疾病之情況下投與抗反轉錄病毒劑。舉例而言,投與用於治療癌症之GDF-8及TGF-β1抑制劑在以單一試劑形式使用時並不始終產生直接抗腫瘤作用。然而,當與化學治療藥物(抗瘤形成藥)組合時,所觀測到之抗腫瘤作用高於各試劑單獨作用之總和。
如本文所用,術語「催化袋(catalytic pocket)」、「催化位點」、「活性位點」總共且不可區分地係指酶中之區域,該區域含有負責受質結合(電荷、疏水性、位阻)之胺基酸殘基及充當質子供體或受體或負責結合輔因子及參與化學反應催化的催化性胺基酸殘基。
如本文所用,短語「醫藥學上可接受之鹽」係指醫藥學上可接受之酸及鹼加成鹽及溶劑合物兩者。此類醫藥學上可接受之鹽包括以下酸之鹽,諸如鹽酸、磷酸、氫溴酸、硫酸、亞磺酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、檸檬酸、酒石酸、順丁烯二酸、氫碘酸、烷酸,諸如乙酸、HOOC-(CH2)n-COOH(其中n為0-4),及其類似物。無毒醫藥鹼加成鹽包括以下鹼之鹽,諸如鈉、鉀、鈣、銨及其類
似物。熟習此項技術者將認識到多種無毒的醫藥學上可接受之加成鹽。
結構式(I)至結構式(II)之化合物可以含有一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑的劑量單位調配物形式例如經口、局部、非經腸(藉由吸入或噴霧)或經直腸投與。如本文所用之術語非經腸包括經皮、皮下、血管內(例如靜脈內)、肌內、或鞘內注射或輸注技術及其類似技術。
醫藥組合物可使用本發明所揭示之化合物來製得。舉例而言,在一個實施例中,醫藥組合物包括醫藥學上可接受之載劑、稀釋劑或賦形劑及如上文參考結構式(I)至結構式(II)所描述之化合物。
在本文所揭示之醫藥組合物中,一或多種結構式(I)至結構式(II)之化合物可與一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑及(必要時)其他活性成分結合存在。含有結構式(I)至結構式(II)之化合物的醫藥組合物可呈適合於經口使用之形式,例如呈錠劑、糖衣錠、口含錠、水性或油性懸浮液、可分散性粉末或顆粒、乳液、硬或軟膠囊、或糖漿或酏劑形式。
意欲用於經口使用之醫藥組合物可根據用於製造醫藥組合物之任何適合之方法來製備,且此類組合物可含有一或多種選自由甜味劑、調味劑、著色劑及防腐劑組成之群的試劑以便提供醫藥上精緻且適口之製劑。錠劑含有與適合於製造錠劑的醫藥學上可接受之無毒賦形劑混雜的活性成分。此等賦形劑可為例如惰性稀釋劑,諸如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉;粒化劑及崩解劑,例如玉米澱粉或褐藻酸;黏合劑,例如澱粉、明膠或阿拉伯膠;及潤滑劑,例如硬脂酸鎂、硬脂酸或滑石。錠劑可未經包衣包覆,或其可藉由已知技術包覆。在一些情況下,此類包衣可藉由適合之技術製備以延遲在胃
腸道中之崩解及吸收,且從而在較長時段內提供持續性作用。舉例而言,可採用時間延遲材料,諸如單硬脂酸甘油酯或二硬脂酸甘油酯。
用於經口使用之調配物亦可以硬明膠膠囊形式呈現,其中活性成分與惰性固體稀釋劑(例如碳酸鈣、磷酸鈣或高嶺土)混合;或以軟明膠膠囊形式呈現,其中活性成分與水或油狀介質(例如花生油、液體石蠟或橄欖油)混合。
用於經口使用之調配物亦可以口含錠形式呈現。
水性懸浮液含有與適合於製造水性懸浮液之賦形劑混雜的活性材料。此類賦形劑可為懸浮劑,例如羧甲基纖維素鈉、甲基纖維素、羥基丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠以及阿拉伯膠;分散劑或濕潤劑,諸如天然產生之磷脂,例如卵磷脂,或環氧烷與脂肪酸之縮合產物,例如聚氧乙烯硬脂酸酯,或氧化乙烯與長鏈脂族醇之縮合產物,例如十七伸乙基氧基十六醇,或氧化乙烯與衍生自脂肪酸及己糖醇(hexitol)之偏酯的縮合產物,諸如聚氧乙烯山梨糖醇單油酸酯,或氧化乙烯與衍生自脂肪酸及己糖醇酐之偏酯的縮合產物,例如聚乙烯脫水山梨糖醇單油酸酯。水性懸浮液亦可含有一或多種防腐劑,例如對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯;一或多種著色劑;一或多種調味劑;及一或多種甜味劑,諸如蔗糖或糖精。
油性懸浮液可藉由使活性成分懸浮於植物油(例如花生油、橄欖油、芝麻油或椰子油)中或礦物油(諸如液體石蠟)中來調配。油性懸浮液可含有增稠劑,例如蜂蠟、硬石蠟或鯨蠟醇。可向所提供之適口口服製劑中添加甜味劑及調味劑。此等組合物可藉由添加抗氧化劑(諸如抗壞血酸)來保存。
適合於藉由添加水製備水性懸浮液之可分散性粉末及顆粒提供與分散劑或濕潤劑、懸浮劑及一或多種防腐劑混雜的活性成分。適合之分散劑或濕潤劑或懸浮劑由上文已提及之彼等試劑例示。亦可存在
另外之賦形劑,例如甜味劑、調味劑以及著色劑。
醫藥組合物亦可呈水包油乳液形式。油相可為植物油或礦物油或此等油之混合物。適合之乳化劑可以為天然存在之膠狀物,例如阿拉伯膠或黃蓍膠;天然存在之磷脂,例如大豆、卵磷脂;以及衍生自脂肪酸及己糖醇酐之酯或偏酯,例如脫水山梨糖醇單油酸酯;及該等偏酯與氧化乙烯之縮合產物,例如聚氧乙烯脫水山梨糖醇單油酸酯。乳液亦可含有甜味劑及調味劑。
在一些實施例中,醫藥學上可接受之載劑、稀釋劑或賦形劑不為水。在其他實施例中,水佔組合物之小於50%。在一些實施例中,包含小於50%水之組合物具有至少1%、2%、3%、4%或5%水。在其他實施例中,水含量以痕量存在於組合物中。
在一些實施例中,醫藥學上可接受之載劑、稀釋劑或賦形劑不為醇。在其他實施例中,醇佔組合物之小於50%。在一些實施例中,包含小於50%醇之組合物具有至少1%、2%、3%、4%或5%醇。在其他實施例中,醇含量以痕量存在於組合物中。
糖漿及酏劑可用例如丙三醇、丙二醇、山梨糖醇、葡萄糖或蔗糖之甜味劑來調配。此類調配物亦可含有緩和劑、防腐劑、調味劑及著色劑。醫藥組合物可呈無菌可注射水性或油性懸浮液形式。此懸浮液可根據已知技術使用上文已提及的彼等適合之分散劑或濕潤劑及懸浮劑來調配。無菌可注射製劑亦可為於非經腸可接受之無毒稀釋劑或溶劑中的無菌可注射溶液或懸浮液,例如呈於1,3-丁二醇中之溶液的形式。在可採用的可接受之媒劑及溶劑當中為水、林格氏溶液(Ringer's solution)及等張氯化鈉溶液。另外,可採用無菌不揮發性油作為溶劑或懸浮介質。出於此目的,可採用任何溫和不揮發性油,包括合成之單甘油酯或二甘油酯。另外,諸如油酸之脂肪酸可用於製備可注射劑。
結構式(I)至結構式(II)之化合物亦可以栓劑形式投與,例如用於藥物之經直腸投與。可藉由將化合物與適合之無刺激性賦形劑混合來製備此等組合物,該賦形劑在常溫下為固體但在直腸溫度下為液體且因此將在直腸中熔化以釋放藥物。此類材料包括可可脂及聚乙二醇。
結構式(I)至結構式(II)之化合物亦可以無菌介質形式非經腸投與。視所用媒劑及濃度而定,藥物可懸浮或溶解於媒劑中。有利的是,可將諸如局部麻醉劑、防腐劑及緩衝劑之佐劑溶解於媒劑中。
組合物可以單位劑型調配,各劑量含有約5至約100mg,更通常約10至約30mg之活性成分。術語「單位劑型」係指適合以單位劑量形式用於人類個體及其他哺乳動物的物理上不連續之單元,各單元含有經計算以產生所需治療作用的預定量之活性材料,其與適合之醫藥賦形劑結合。
活性化合物可在寬劑量範圍內有效,且一般以醫藥學上有效量投與。然而,應理解,實際上投與之化合物量將由醫師根據相關情況來決定,該等相關情況包括待治療之病症、所選擇投藥途徑、投與的之實際化合物、個體患者之年齡、重量及反應患者症狀之嚴重性及其類似情況。
為了製備固體組合物(諸如錠劑),將主要活性成分與醫藥賦形劑混合以形成含有本文所描述之化合物的均勻混合物的固體預調配組合物。當將此等預調配組合物稱為均勻組合物時,活性成分通常均勻分散在整個組合物中,以便該組合物可容易地再分成同等有效之單位劑型,諸如錠劑、丸劑及膠囊。隨後,將此固體預調配物再分成含有例如0.1至約500毫克本文所描述之化合物之活性成分的上文所描述之類型之單位劑型。
錠劑或丸劑可經包衣包覆或以其他方式混配,以提供獲得長效益處之劑型。舉例而言,錠劑或丸劑可包含內部劑量及外部劑量組
分,後者呈前者上之包膜形式。兩種組分可由腸溶層隔開,該腸溶層用以防止在胃中崩解且允許內部組分完整進入十二指腸或釋放延遲。各種材料可用於此類腸溶層或腸溶包衣,此類材料包括多種聚合酸及聚合酸與諸如蟲膠、鯨蠟醇及乙酸纖維素之材料的混合物。
向患者投與的化合物或組合物之量將視所投與之物質、投藥目的(諸如預防或治療)、患者狀態、投藥方式及其類似者而變化。在治療性應用中,可向已患有疾病之患者以足以治癒或至少部分地遏制疾病及其併發症之症狀的量投與組合物。有效劑量將視所治療之疾病病狀而定,以及由主治臨床醫師視諸如疾病嚴重性、患者之年齡、體重及一般條件及其類似者的因素而定。
向患者投與之組合物可呈上文所描述之醫藥組合物形式。此等組合物可藉由習知滅菌技術滅菌,或可經無菌過濾。水溶液可封裝以按原樣使用或凍乾,經凍乾之製劑在投藥之前與無菌水性載劑組合。化合物製劑之pH通常將在3與11之間,更佳為5至9,且最佳為7至8。應理解,使用某些前述賦形劑、載劑或穩定劑將導致醫藥鹽形成。
化合物之治療劑量可根據例如進行治療之特定用途、化合物之投藥方式、個體之健康狀況及條件、及處方醫師之判斷而變化。本文所描述之化合物在醫藥組合物中的比例或濃度可視包括劑量、化學特徵(例如疏水性)及投藥途徑之多種因素而變化。舉例而言,本文所描述之化合物可以含有約0.1%至約10% w/v之化合物的水性生理緩衝溶液形式提供以用於非經腸投與。一些典型劑量範圍為每天每公斤體重約1μg至約1g。在一些實施例中,劑量範圍為每天每公斤體重約0.01mg至約100mg。劑量很可能視諸如以下各者之變數而定:疾病或病症之類型及發展程度、特定患者之總體健康狀況、所選擇之化合物的相對生物功效、賦形劑之配方及其投藥途徑。有效劑量可自來源於活體外或動物模型測試系統之劑量反應曲線外推得到。
本文所描述之化合物亦可與一或多種另外之活性成分組合調配,該等活性成分可包括任何醫藥劑,諸如抗病毒劑、疫苗、抗體、免疫增強劑、免疫抑制劑、消炎劑及其類似試劑。
提供適用於合成所揭示之化合物的通常已知之化學合成流程及條件的多種通用參考文獻可供使用(參見例如Smith及March,March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,第五版,Wiley-Interscience,2001;或Vogel,A Textbook of Practical Organic Chemistry,Including Qualitative Organic Analysis,第四版,New York:Longman,1978)。
如本文所描述之化合物可藉由此項技術中已知之任何手段來純化,包括層析手段,諸如HPLC、製備型薄層層析、急驟管柱層析及離子交換層析。可使用任何適合之固定相,包括正相及反相以及離子性樹脂。所揭示之化合物最通常經由矽膠及/或氧化鋁層析來純化。參見例如Introduction to Modern Liquid Chromatography,第2版,L.R.Snyder及J.J.Kirkland編,John Wiley and Sons,1979;及Thin Layer Chromatography,E.Stahl編,Springer-Verlag,New York,1969。
在用於製備標的化合物之任何製程期間,可能必要及/或需要保護所涉及之任何分子上的敏感性或反應性基團。此可藉助於如標準著作中所描述之習知保護基來達成,諸如J.F.W.McOmie,「Protective Groups in Organic Chemistry」,Plenum Press,London and New York 1973;T.W.Greene及P.G.M,Wuts,「Protective Groups in Organic Synthesis」,第三版,Wiley,New York 1999;「The Peptides」;第3卷(編者:E.Gross及J.Meienhofer),Academic Press,London and New York 1981;「Methoden der organischen Chemie」,Houben-Weyl,第4
版,第15/l卷,Georg Thieme Verlag,Stuttgart 1974;H.-D.Jakubke及H.Jescheit,「Aminosauren,Peptide,Proteine」,Verlag Chemie,Weinheim,Deerfield Beach,and Basel 1982;及/或in Jochen Lehmann,「Chemie der Kohlenhydrate:Monosaccharide and Derivate」,Georg Thieme Verlag,Stuttgart 1974。可在適宜後續階段使用此項技術已知之方法移除保護基。
本文所揭示之化合物可使用一般熟習此項技術者熟悉之程序且如本文所描述來製得。舉例而言,結構式(I°)、結構式(I)或結構式(II)中之任一者的化合物可根據本文之流程或類似合成流程來製備。
熟習此項技術者可調整本文之流程的反應次序以配合所需目標分子。當然,在某些情況中,熟習此項技術者將使用不同試劑來影響一或多個個別步驟或使用某些取代基之受保護型式。另外,熟習此項技術者將認識到,結構式(I)、結構式(II)或結構式(I°)的化合物或醫藥學上可接受之鹽可一起使用不同途徑來合成。
適合用於本發明所揭示之醫藥組合物中的化合物包括上文所揭示之化合物。此等化合物可根據上文所描述之通用流程來製得,例如使用類似於下文在實例中所描述之程序的程序。
以下實例意欲進一步說明某些實施例,且不意欲限制本發明所揭示之化合物的範疇。
本發明化合物適用於在人類或動物中預防、診斷及治療多種醫學病症。相對於不與相同化合物結合之GDF蛋白質,化合物為用於抑制或減少與GDF蛋白質相關聯之一或多種活動。視情況,相對於不與相同化合物結合之成熟GDF-8蛋白質,化合物抑制或減少成熟GDF-8之一或多種活性(不論是呈單體形式,活性二聚形式,還是在GDF-8潛伏性複合物中複合)。在一個實施例中,相對於不與一或多種本發
明所揭示之化合物結合的成熟GDF-8蛋白質,當與一或多種本發明所揭示之化合物結合時,成熟GDF-8蛋白質之活性受到至少50%抑制,視情況至少60%、62%、64%、66%、68%、70%、72%、72%、76%、78%、80%、82%、84%、86%或88%抑制,視情況至少90%、91%、92%、93%或94%抑制,且視情況至少95%至100%抑制。
由本發明所揭示之化合物診斷、治療或預防的醫學病症視情況為肌肉及神經肌肉病症;脂肪組織病症,諸如肥胖;2型糖尿病、葡萄糖耐量異常、代謝症候群(例如症候群X)、由外傷(諸如灼傷)誘發之胰島素抗性;或骨骼退化疾病,諸如骨質疏鬆。醫學病狀視情況為肌肉或神經肌肉病症,諸如肌肉營養不良、肌肉萎縮症、充血性阻塞性肺病、肌肉萎縮症候群、肌肉減少症或惡病體質;及與骨流失相關聯之病症,其包括骨質疏鬆(尤其在老年及/或停經後女性中)、糖皮質激素誘發之骨質疏鬆、骨質減少及骨質疏鬆相關骨折。適合用本發明之GDF-8抑制劑治療的其他目標代謝骨骼疾病及病症包括因慢性糖皮質激素療法所致之低骨質量、性腺早衰(premature gonadal failure)、雄激素抑制、維生素D不足、繼發性副甲狀腺亢進症、營養不足及神經性厭食症。抗體視情況用於在哺乳動物中,視情況在人類中預防、診斷或治療此類醫學病症。
本發明之化合物或組合物以治療有效量進行投與。如本文所用,抗體之「有效量」為足以降低GDF蛋白質之活性以達成所需生物學結果(例如增加肌肉質量或強度)的劑量。一般而言,治療有效量可隨個體年齡、條件及性別以及個體中醫學病狀之嚴重性而變化。劑量可由醫師決定且視需要調整以適合所觀測之治療作用。一般而言,投與組合物以使得化合物以介於1μg/kg與20mg/kg之間的劑量給予。視情況,以單次給藥形式給予化合物,以使化合物之循環量在給藥之後最大化持續最大時間長度。亦可在單次給藥之後使用連續輸注。
用本發明所揭示之化合物治療、診斷或預防上文醫學病狀的方法亦可用於TGF-β超級家族中之其他蛋白質。許多此等蛋白質(例如BMP-11)在結構中與GDF-8相關。因此,在另一個實施例中,本發明包含治療前述病症之方法,其藉由向個體單獨或與其他TGF-β抑制劑(諸如針對GDF-8之中和抗體)組合投與能夠抑制BMP-11或活化素之化合物來進行。
因此,在一個態樣中,本發明提供用於抑制細胞中GDF-8之方法,其包含使該細胞與有效量的式(I)、式(II)或式(I°)或其任一實施例之化合物或醫藥學上可接受之鹽、或包含該化合物或醫藥學上可接受之鹽的醫藥組合物接觸。在另一態樣中,本發明包含用於治療患有疾病或病症之患者的方法,其中該患者將會因肌肉組織質量或強度提高而受到醫療效益,該方法包含向患者投與治療有效量的式(I)、式(II)或式(I°)或其任一實施例之化合物或醫藥學上可接受之鹽、或包含該化合物或醫藥學上可接受之鹽的醫藥組合物。疾病或病症可為肌肉病症、脂肪組織病症、神經肌肉病症、代謝病症、糖尿病或骨骼退化病症。在某些實施例中,疾病或病症為肌肉病症,諸如(但不限於)肌肉營養不良、肌肉萎縮症、充血性阻塞性肺病、肌肉萎縮症候群、肌肉減少症或惡病體質。在某些其他實施例中,疾病或病症為肌肉營養不良。在其他實施例中,疾病或病症為肥胖、2型糖尿病、葡萄糖耐量異常、症候群X、由外傷誘發之胰島素抗性、或骨質疏鬆。在特定實施例中,疾病或病症為骨質疏鬆。
在又其他實施例中,疾病或病症為因慢性糖皮質激素療法所致之低骨質量、性腺早衰、雄激素抑制、維生素D不足、繼發性副甲狀腺亢進症、營養不足及神經性厭食症。
在另一態樣中,本發明包含用於在哺乳動物中增加肌肉質量之方法,其包含投與治療有效量的式(I)、式(II)或式(I°)或其任一實施例
之化合物或醫藥學上可接受之鹽、或包含該化合物或醫藥學上可接受之鹽的醫藥組合物。在另一態樣中,本發明包含用於在哺乳動物中增加肌肉強度之方法,其包含投與治療有效量的式(I)、式(II)或式(I°)或其任一實施例之化合物或醫藥學上可接受之鹽、或包含該化合物或醫藥學上可接受之鹽的醫藥組合物。在另一態樣中,本發明包含用於在有需要之患者中增加小樑骨密度的方法,其包含投與治療有效量的式(I)、式(II)或式(I°)或其任一實施例之化合物或醫藥學上可接受之鹽、或包含該化合物或醫藥學上可接受之鹽的醫藥組合物。在任何前述方法及其實施例,個體可為哺乳動物。如本文中所用,術語「個體(individual)」或「患者」或「個體(subject)」可互換使用,且係指任何動物,包括哺乳動物,較佳為小鼠、大鼠、其他嚙齒動物、兔、犬、貓、豬、牛、羊、馬或靈長類動物,且最佳為人類。
以下實例意欲進一步說明某些實施例,且不意欲限制本發明所揭示之化合物的範疇。
催化劑1:Pd(PPh3)4或Pd2(dba)3/2-二環己基膦基-2',6'-二甲氧基二苯基(SPhos)或Pd(OAc)2/2-二環己基膦基-2',6'-二甲氧基二苯基(SPhos)或Pd2(dba)3/2-二環己基膦基-2',6'-二甲氧基二苯基(Xphos),
Pd(OAc)2/2-二環己基膦基-2',6'-二甲氧基二苯基(Xphos)或氯(2-二環己基膦基-2',6'-二甲氧基-1,1'-聯二苯)[2-(2'-胺基-1,1'-聯二苯)]鈀(II)(SPhos-Pd-G2)或氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯二苯)[2-2'-胺基-1,1'-聯二苯)]鈀(II)(XPhos-Pd-G2)或Pd2(dba)3/2'-二環己基膦基-2,6-二甲氧基-1,1'-聯二苯-3-磺酸鈉水合物或Pd(OAc)2/2'-二環己基膦基-2,6-二甲氧基-1,1'-聯二苯-3-磺酸酯鈉水合物催化劑2:Pd(PPh3)4或Pd2(dba)3/2-二環己基膦基-2',6'-二甲氧基二苯基(SPhos)或Pd(OAc)2/2-二環己基膦基-2',6'-二甲氧基二苯基(SPhos)或Pd2(dba)3/2-二環己基膦基-2',6'-二甲氧基二苯基(Xphos),Pd(OAc)2/2-二環己基膦基-2',6'-二甲氧基二苯基(Xphos)或氯(2-二環己基膦基-2',6'-二甲氧基-1,1'-聯二苯)[2-(2'-胺基-1,1'-聯二苯)]鈀(II)(SPhos-Pd-G2)或氯(2-二環己基膦基-2',4'-6'-三異丙基-1,1'-聯二苯)[2-2'-胺基-1,1'-聯二苯)]鈀(II)(XPhos-Pd-G2)
方法A:管柱:Luna 5μm C8(100×4.6mm),流動速率1.0mL/min,移動相:A:H2O 0.05% TFA,B:CH3CN 0.05% TFA
方法B:管柱:Gemini 5μm C18(100×4.6mm),流動速率1.5mL/min,移動相:A:H2O 0.05% HCOOH,B:CH3CN 0.05% HCOOH
在氬氣氛圍下將4-(2-氯吡啶-3-基)喹諾酮(200mg,0.83mmol)、Pd2(dba)3(30mg,0.03mmol)及2-二環己基膦基-2',4',6'-三異丙基聯苯(XPHOS,62mg,0.13mmol)轉移至含有攪拌棒之微波小瓶(20mL)中。隨後將小瓶密封且藉由真空抽去空氣。向以上反應物中添加溴化6-甲基-2-吡啶基鋅(THF中之0.5M溶液,4.0mL,2.0mmol),且在真空下脫氣,接著經由氣囊引入氬氣。在三個脫氣循環之後,在微波(150℃)中加熱反應混合物持續40分鐘。用羅謝爾鹽之飽和水溶液(5mL)稀釋反應混合物,且在減壓下濃縮以移除揮發物。用EtOAc(30
mL)稀釋粗濃縮物,且分離有機層。用EtOAc(30mL)進一步萃取水層。用NaCl水溶液(10mL)洗滌經合併之有機層,經MgSO4攪拌,經由Fluorosil®/Celite®墊過濾,濃縮,且藉由反相製備型HPLC來純化。濃縮產物溶離份,用水稀釋,且用NaHCO3水溶液中和。藉由過濾來收集所得固體,且乾燥,得到呈白色固體狀之4-(6'-甲基-[2,2'-聯吡啶]-3-基)喹諾酮(78mg,31%)。1H NMR(300MHz,DMSO-d 6)δ 8.84(dd,J=4.7,1.7Hz,1H),8.81(d,J=4.3Hz,1H),7.99(dt,J=8.4,0.9Hz,1H),7.89(dd,J=7.7,1.7Hz,1H),7.78(d,J=8.0Hz,1H),7.70-7.52(m,3H),7.34(dd,J=4.4,0.9Hz,2H),7.26(d,J=4.4Hz,1H),6.90(d,J=7.6Hz,1H),1.59(s,3H)。
將6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈(175mg,0.69mmol)、氯(2-二環己基膦基-2',6'-二甲氧基-1,1'-聯二苯)[2-(2'-胺基-1,1'-聯二苯)]鈀(II)(SPhos-Pd-G2,35mg,0.05mmol)、無水THF(10mL)及攪拌棒轉移至螺旋蓋小瓶中,且用可穿刺之特氟隆(teflon)蓋密封。在三個脫氣循環中,藉由施加真空及引入氬氣來使小瓶中攪拌之內容物脫氣。隨後,在氬氣下經3分鐘之時段用溴化6-甲基-2-吡啶基鋅(THF中之0.5M溶液,2.77mL,1.38mmol)處理經脫氣之不均勻漿液。使棕色透明均勻反應混合物再次脫氣,且加熱以在70℃下攪拌24小時。在藉由LC/MS分析冷卻至室溫之反應混合物後,注意到多個峰以及6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈之90%消耗。在此階段,在減壓下濃縮棕色均勻反應混合物,且用飽和Na2CO3水溶液(10mL)淬滅。用CH2Cl2(50mL)稀釋不均勻漿液,攪拌且自部分可分離
(semi-separable)之不均勻混合物分離有機層。用CH2Cl2(2×50mL)萃取剩餘水層。經MgSO4/Celite®攪拌經合併之有機層,過濾且濃縮。在Redifsep® 24G矽膠管柱上且在用100% CH2Cl2-1% 7N NH3 MeOH/CH2Cl2溶離的情況下藉由Combiflash®來純化所得粗物質。在減壓下濃縮含有產物及MH+ 185雜質(MH+185)之溶離份。在EtOAc(4mL)中攪拌所得淺黃色固體(100mg),過濾且抽吸乾燥,得到呈灰白色固體狀之6-(6'-甲基-[2,2'聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈(68mg,31%)。1H NMR(300MHz,DMSO-d 6)δ 8.74(dd,J=4.7,1.6Hz,1H),8.55(dd,J=1.6,1.0Hz,1H),8.44(d,J=0.4Hz,1H),8.05(dd,J=7.8,1.6Hz,1H),7.77-7.63(m,3H),7.59(dd,J=7.8,4.7Hz,1H),7.21(dd,J=9.3,1.7Hz,1H),7.15(d,J=7.5Hz,1H),2.08(s,3H)。LCMS:rt 3.80分鐘(A),純度96%,MS(m/e)312(MH+)。
含有攪拌棒之兩頸圓底燒瓶在一個頸處安裝有回流冷凝器,且在另一個頸處安裝有橡膠隔片。將三通活栓附接於回流冷凝器上,且將其餘兩個入口連接至氬氣氣囊及真空泵軟管上。將6-(2-氯吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡啶(1.0g,4.34mmol)及Pd(PPh3)4(0.15g,0.13mmol)轉移至反應燒瓶中,在真空下引入無水THF(20mL),且藉由在三個循環中施加真空接著引入氬氣來脫氣。隨後,在氬氣下經3分鐘之時段用溴化6-甲基-2-吡啶基鋅(THF中之0.5M溶液,17mL,8.5mmol)處理經脫氣之不均勻漿液。使所得深色不均勻懸浮液再次脫氣,且在70℃下攪拌隔夜。在藉由LC/MS分析冷卻至室溫之反應混合物後,注意到多個峰以及6-(2-氯吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡
啶之77%消耗。在此階段,在減壓下濃縮棕色反應混合物,且用飽和Na2CO3水溶液(35mL)/CH2Cl2(130mL)淬滅,且攪拌20分鐘。自不均勻漿液分離有機層,且用CH2Cl2(2×75mL)萃取水層。經MgSO4/Celite®攪拌經合併之有機層,過濾且濃縮。將所得粗混合物吸附在矽膠上,且在RediSep® 40G矽膠管柱上且在用100% CH2Cl2-2% 7N NH3 MeOH/CH2Cl2溶離的情況下藉由Combiflash®來純化。在減壓下濃縮含有MH+185雜質之產物溶離份。將由此獲得之灰白色固體(370mg)在EtOAc(25mL)中在70℃下攪拌5分鐘,過濾熱混合物且抽吸乾燥,得到6-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶(315mg,25%)。1H NMR(300MHz,DMSO-d 6)δ 8.90(dd,J=1.7,0.9Hz,1H),8.74(dd,J=4.7,1.6Hz,1H),8.47(s,1H),8.01(dd,J=7.8,1.7Hz,1H),7.79-7.69(m,2H),7.66(dd,J=9.2,0.8Hz,1H),7.58(dd,J=7.8,4.8Hz,1H),7.26(dd,J=9.2,1.8Hz,1H),7.13(dd,J=7.2,1.4Hz,1H),2.02(s,3H)。LCMS:rt 3.06分鐘(A),純度97%,MS(m/e)288(MH+)。
以與製備6-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶類似之方式藉由7-(2-氯吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡啶(1.0g,4.34mmol)及溴化6-甲基-2-吡啶基鋅((THF中之0.5M溶液,17mL,8.5mmol)在Pd(PPh3)4(0.15g,0.13mmol)存在下之反應來製備及分離7-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶(229mg,18%)。白色固體。1H NMR(300MHz,DMSO-d 6)δ 8.77(dd,J=7.1,0.8Hz,1H),8.74(dd,J=4.8,1.6Hz,1H),8.46(s,1H),8.00(dd,J=
7.8,1.6Hz,1H),7.78-7.66(m,3H),7.59(dd,J=7.8,4.7Hz,1H),7.14(dd,J=7.3,1.3Hz,1H),6.78(dd,J=7.1,1.9Hz,1H),2.01(s,3H)。LCMS:rt 3.08分鐘(A),純度99%,MS(m/e)288(MH+)。
在室溫下經3分鐘向微波小瓶(20mL)中之攪拌TFA(0.8mL)中添加濃H2SO4(0.2mL),且將淺棕色均勻酸性混合物再攪拌5分鐘之時段。在室溫下向以上酸性溶液中逐份添加固體6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈(125mg,0.40mmol)持續5分鐘,且攪拌不均勻混合物10分鐘。隨後,在85℃下加熱混合物。在2小時之後藉由LC/MS來分析反應混合物,其指示6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈完全消耗。使反應混合物冷卻至室溫且將其傾倒至冰水上。隨後,用50% NaOH水溶液使酸性均勻水溶液鹼化(pH>9),且在室溫下攪拌2小時。藉由抽吸過濾來收集所得灰白色沈澱,用水洗滌,乾燥,且在RediSep® 12G矽膠管柱上且在用100% CH2Cl2接著用7% 7N NH3 MeOH/CH2Cl2溶離的情況下藉由Combiflash®來純化。在乾燥在濃縮產物溶離份之後所獲得的固體後,分離出6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺之白色固體(60mg,45%)。1H NMR(300MHz,DMSO-d 6)δ 9.37(d,J=1.5Hz,1H),8.73(dd,J=4.7,1.6Hz,1H),8.30(s,1H),8.02-7.85(重疊br s,1H),7.96(dd,J=7.8,1.6Hz,1H),7.69(t,J=7.7Hz,1H),7.60(app s,1H),7.59-7.55(m,1H),7.53(d,J=9.8Hz,1H),7.45-7.28(br s,1H),7.11(d,J=8.1Hz,1H),7.08(dd,J=9.3,1.9Hz,1H),2.08(s,3H)。LCMS:rt 1.88分鐘(A),純度96%,MS(m/e)330(MH+)。
以與製備6-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶類似之方式藉由6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈(1.0g,3.93mmol)及溴化2-吡啶基鋅(THF中之0.5M溶液,13mL,6.5mmol)在Pd(PPh3)4(0.14g,0.12mmol)存在下之反應來製備及分離6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈。灰白色固體(435mg,37%)。1H NMR(300MHz,DMSO-d 6)δ 8.75(dd,J=4.7,1.6Hz,1H),8.56(dd,J=1.7,1.0Hz,1H),8.43(s,1H),8.28(dt,J=4.8,1.4Hz,1H),8.09(dd,J=7.8,1.6Hz,1H),7.89(app d,J=1.4Hz,1H),7.88(app d,J=1.2Hz,1H),7.64(dd,J=9.2,0.8Hz,1H),7.61(app dd,J=7.8,4.8Hz,1H),7.29(app dd,J=9.2,4.8Hz,1H),7.14(dd,J=9.3,1.7Hz,1H)。LCMS:rt 3.85分鐘(A),純度95%,MS(m/e)330(MH+)。
以與製備6-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶類似之方式藉由6-(2-氯吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡啶(1.0g,4.34mmol)及溴化2-吡啶基鋅((THF中之0.5M溶液,17mL,8.5mmol)在Pd(PPh3)4(0.15g,0.13mmol)存在下之反應來製備及分離6-([2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶(395mg,31%)。灰白色固體。1H NMR(300MHz,DMSO-d 6)δ 8.93(dd,J=1.8,0.9Hz,1H),
8.74(dd,J=4.8,1.6Hz,1H),8.47(s,1H),8.25(dt,J=4.8,1.5Hz,1H),8.04(dd,J=7.8,1.6Hz,1H),7.90(d,J=1.3Hz,1H),7.88(app d,J=1.2Hz,1H),7.64(dd,J=9.2,0.8Hz,1H),7.60(app dd,J=7.8,4.8Hz,1H),7.29(app dd,J=9.2,4.8Hz,1H),7.21(dd,J=9.2,1.8Hz,1H)。LCMS:rt 3.11分鐘(A),純度96%,MS(m/e)274(MH+)。
以與製備6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺類似之方式自6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈(200mg,0.67mmol)製備及分離6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺。白色固體(98mg,46%)。1H NMR(300MHz,DMSO-d 6)δ 9.39(dd,J=1.8,0.9Hz,1H),8.74(dd,J=4.7,1.6Hz,1H),8.31(s,1H),8.26(dt,J=4.8,1.4Hz,1H),8.00-7.92(重疊br s,1H),7.99(dd,J=7.8,1.6Hz,1H),7.87(dd,J=7.9,1.7Hz,1H),7.85-7.79(m,1H),7.59(dd,J=7.8,4.8Hz,1H),7.51(dd,J=9.3,0.9Hz,1H),7.37(br s,1H),7.28(ddd,J=6.7,4.8,2.1Hz,1H),7.02(dd,J=9.3,1.9Hz,1H)。LCMS:rt 1.88分鐘(A),純度97%,MS(m/e)316(MH+)。
如以下流程中所描繪來製備6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4-胺:
6-氯-4-甲氧基吡啶并[3,2-d]嘧啶:在氮氣氛圍下將含4,6-二氯吡啶并[3,2-d]嘧啶(自PCT國際申請案2005058913、PCT國際申請案2011131741、PCT國際申請案201009469製備)(2.5g,12.4mmol)及NaHCO3(3.1g,31mmol)之MeOH(20mL)在70℃下加熱12小時。過濾反應混合物,且濃縮濾液。用水稀釋粗濃縮物,且過濾。在EtOAc(20mL)中攪拌抽吸乾燥之固體,且過濾,獲得呈灰白色固體狀之6-氯-4-甲氧基吡啶并[3,2-d]嘧啶(1.8g)。1H NMR(300MHz,DMSO-d 6):δ 8.88(s,1H),8.37(d,J=8.8Hz,1H),8.00(d,J=8.8Hz,1H),4.14(s,3H)。
6-(2-氯吡啶-3-基)-4-甲氧基吡啶并[3,2-d]嘧啶:向反應燒瓶中裝入6-氯-4-甲氧基吡啶并[3,2-d]嘧啶(3.5g,17.8mmol)、2-氯-3-吡啶酸頻哪醇酯(4.35g,18.2mmol)、Na2CO3(4.0g,38.2mmol)及1,4-二噁烷(100mL)及攪拌棒。在攪拌下藉由真空使內容物脫氣且用氬氣回填三次。隨後,向反應內容物中添加Pd(PPh3)3(0.87g,0.75mmol),重複脫氣循環,且在氬氣下在98℃下加熱隔夜。使黃色不均勻反應混合物冷卻至室溫,且在布赫納漏斗(Buchner funnel)上抽吸過濾。用另外量之二噁烷(30mL)洗滌在漏斗上收集之固體。使淺黃色透明濾液溶液穿過Celite®墊,且濃縮。將由此獲得之淺黃色粗固體殘餘物分配於CH2Cl2(150mL)/水(50mL)之間。分離有機層,經MgSO4乾燥,過濾且濃縮。在EtOAc(30mL)中攪拌粗濃縮物,且抽吸過濾。用
EtOAc(10mL)洗滌濾餅,且乾燥,獲得1.6g呈白色固體狀之6-(2-氯吡啶-3-基)-4-甲氧基吡啶并[3,2-d]嘧啶(純度:95%)。濃縮濾液,且藉由急驟管柱層析(Combiflash® companion system®,使用RediSep®矽膠管柱40g,0%-30%-60% EtOAc/己烷溶離溶劑梯度)來純化濃縮物,獲得另外0.65g之標題化合物。1H NMR(300MHz,DMSO-d 6):δ 8.92(s,1H),8.57(dd,J=4.8,2.0Hz,1H),8.45(d,J=8.7Hz,1H),8.28(d,J=8.7Hz,1H),8.13(dd,J=7.6,2.0Hz,1H),7.63(dd,J=7.6,4.8Hz,1H),4.16(s,3H)。
4-甲氧基-6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶:含有攪拌棒之兩頸圓底燒瓶在一個頸處安裝有回流冷凝器,且在另一個頸處安裝有橡膠隔片。將三通活栓附接於回流冷凝器上,且將其餘兩個入口連接至氬氣氣囊及真空泵軟管上。將6-(2-氯吡啶-3-基)-4-甲氧基吡啶并[3,2-d]嘧啶(2.0g,7.3mmol)及SPhos-Pd-G2(0.16g,0.22mmol)轉移至反應燒瓶中,在真空下引入無水THF(20mL),藉由在三個循環中施加真空接著引入氬氣來脫氣,且同時開始加熱黃色懸浮液反應混合物。隨後,在氬氣下在34℃下經10分鐘之時段添加溴化6-甲基-2-吡啶基鋅(THF中之0.5M溶液,22mL,11mmol)。使所得淺棕色不均勻混合物再次脫氣,且在45℃下攪拌。在1小時之後,反應混合物變成均勻溶液,且如藉由LC/MS所分析,指示7%未反應之6-(2-氯吡啶-3-基)-4-甲氧基吡啶并[3,2-d]嘧啶。在5小時之後(<3%未反應之6-(2-氯吡啶-3-基)-4-甲氧基吡啶并[3,2-d]嘧啶),使反應混合物冷卻至室溫,在減壓下濃縮,且在飽和Na2CO3水溶液(100mL)/CH2Cl2(300mL)中攪拌。自部分可分離之不均勻混合物分離有機層,且用CH2Cl2(3×200mL)萃取水層。經MgSO4/Celite®攪拌經合併之有機層,過濾且濃縮。將所得粗混合物吸附在矽膠上,且在RediSep® 40G矽膠管柱上且在用100% CH2Cl2-1% 7N NH3 MeOH/CH2Cl2-3% 7N
NH3 MeOH/CH2Cl2溶離的情況下藉由Combiflash®來純化。在含有產物之UV跡線上觀測到兩個峰。使對應於低滯留時間峰之不純產物溶離份濃縮(1.2g),且自EtOAc結晶。藉由過濾來收集所得結晶白色固體,且抽吸乾燥,得到0.60g純度96%之4-甲氧基-6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶。將濾液與來自較高滯留時間峰之不純產物溶離份合併,且以與上文類似之方式再次純化濃縮物(1.4g),獲得另一批次之4-甲氧基-6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶(0.78g,94%純度,白色固體)。合併產率(61%)。1H NMR(300MHz,DMSO-d 6)δ 8.84(s,1H),8.80(dd,J=4.7,1.7Hz,1H),8.10-8.07(m,2H),7.90(ddd,J=7.8,1.2,0.6Hz,1H),7.77(t,J=7.7Hz,1H),7.61(dd,J=7.8,4.7Hz,1H),7.53(d,J=8.8Hz,1H),7.12(ddd,J=7.6,1.1,0.6Hz,1H),4.12(s,3H),1.81(s,3H)。LCMS:rt 3.65分鐘(A),MS(m/e)330(MH+)。
6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4(3H)-酮鹽酸鹽:在室溫下向4-甲氧基-6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶(1.1g,3.33mmol)於EtOH(6mL)中之攪拌不均勻漿液中添加濃HCl(0.05ml),且將漿液逐漸加熱至58℃,且監測反應進程。分別在1小時(0.05mL)、1小時30分鐘(0.1mL)及2小時30分鐘(0.05mL)時向不均勻反應混合物中添加另外量之濃HCl以實現4-甲氧基-6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶之消耗。在於2小時30分鐘時添加濃HCl後,反應混合物變成均勻溶液,且經30分鐘之時段轉化回不均勻混合物。在此階段,繼續加熱持續另外2小時之時段,且冷卻至室溫。藉由過濾來收集來自反應混合物之結晶固體,且抽吸乾燥,得到200mg呈HCl鹽形式之6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4(3H)-酮。在於減壓下濃縮濾液後,得到淺黃色固體,將其在10% EtOH/EtOAc(50mL)中攪拌20分鐘,且藉由過濾來收集,得到另
一批次之6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4(3H)-酮鹽酸鹽(0.81g)。合併產率(1.1g,93%)。LCMS:rt 2.80分鐘(A),純度96%,MS(m/e)316(MH+)。
4-氯-6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶:在室溫下在氬氣下向6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4(3H)-酮鹽酸鹽(1.0g,2.8mmol)及無水CH2Cl2(30mL)之攪拌混合物中添加乙二醯氯(2mL,3.0g,23.6mmol)。在攪拌反應內容物10分鐘之後,經10分鐘之時段向反應混合物中添加溶解於無水CH2Cl2(2mL)中之催化量DMF(0.1mL),且在65℃下加熱3小時。分析由此形成之深色反應混合物以注意6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4(3H)-酮完全消耗,形成次要產物。使反應混合物冷卻,濃縮,用EtOAc(75mL)稀釋,且在固體Na2CO3(5.0g)中攪拌30分鐘。用冰水(30mL)稀釋深色漿液,攪拌20分鐘,分離有機層,且用EtOAc(2×50mL)萃取水層。經MgSO4乾燥經合併之有機層,過濾且濃縮。在RediSep® 40g矽膠管柱上且在用30%-60% EtOAc/己烷溶離的情況下藉由Combiflash®對粗濃縮物進行純化,獲得呈灰白色固體狀之4-氯-6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶(120mg,12%)。LCMS:rt 4.00分鐘(A),純度95%,MS(m/e)334(MH+)。
6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4-胺:將螺旋蓋小瓶中之4-氯-6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶(120mg,0.36mmol)、THF(3mL)及4% NH3/i-PrOH(3mL)在70℃下攪拌4小時。濃縮淺紫色反應混合物,且在RediSep® 4G矽膠管柱上且在用100% CH2Cl2-3% 7N NH3 MeOH/CH2Cl2溶離的情況下藉由藉由Combiflash®來純化,得到呈灰白色固體狀之6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4-胺(53mg,47%)。1H NMR(300MHz,DMSO-d 6)δ 8.76(dd,J=4.7,1.7Hz,1H),8.38(s,1H),8.23(dd,J=
7.8,1.7Hz,1H),7.88-7.72(m,4H),7.61(dd,J=7.8,4.7Hz,1H),7.50(br s,1H),7.38(d,J=8.7Hz,1H),7.14(dd,J=6.4,2.3Hz,1H),1.92(s,3H)。LCMS:rt 1.93分鐘(A),純度99%,MS(m/e)315(MH+)。
製備5-(2-氯吡啶-3-基)-1H-吲唑:
5-溴-1H-吲唑-甲酸第三丁酯:在室溫下在溫和氮氣流下向含有磁性攪拌棒之單頸圓底燒瓶中裝入5-溴-1H-吲唑(3.0g,15.2mmol)、二碳酸二第三丁酯(4.2g,19.2mmol)及乙腈(30mL)。向以上攪拌均勻溶液中一次性添加三乙胺(1.8g,2.5mL,17.7mmol),接著經15分鐘之時段逐份添加4-(二甲基胺基)吡啶(2.2g,18mmol)。在室溫下在氮氣下攪拌均勻灰棕色透明反應混合物,且藉由TLC(50%EtOAc/己烷)監測反應進程。在3小時之後中斷攪拌,且在真空下藉由旋轉蒸發器來濃縮反應混合物。獲得透明黏性液體,且將其溶解於EtOAc/己烷(7:3,200mL)中,且用水(75mL)稀釋。分離有機層,且用EtOAc/己烷(1:1,125mL)萃取水層。用水(100mL),接著用1N HCl水溶液(2×75mL)洗滌經合併之有機層以移除4-(二甲基胺基)吡啶。用水(2×75mL)、飽和NaHCO3水溶液(2×75mL)及飽和NaCl水溶液洗滌經合併之有機層。經無水MgSO4乾燥分離之有機層,過濾,濃縮,且在真空下乾燥,得到呈淺黃色黏性液體狀之5-溴-1H-吲唑-甲酸第三丁酯(4.5g,純度97%),其未經進一步純化即使用。1H NMR(DMSO-d6):
δ 8.36(d,J=0.8Hz,1H),8.11(app d,J=0.8Hz,1H),8.00(d,J=8.8Hz,1H),7.71(app dd,J=8.8,0.8Hz,1H),1.62(s,9H)。LCMS:97%,MS(m/e)241(MH+-t-Bu)。A在氮氣氛圍下向配備有磁性攪拌棒之單頸圓底燒瓶(250mL)中裝入溶解於1,4-二噁烷(130mL)中之5-溴-1H-吲唑-甲酸第三丁酯(4.0g,13.4mmol)、2-氯-3-吡啶酸頻哪醇酯(4g,16.7mmol)、Pd(PPh3)4(1.5g,1.3mmol)及2M Na2CO3水溶液(20mL,40mmol)。用含有三通活栓、配備有氬氣填充氣囊之回流冷凝器置換橡膠隔膜。攪拌反應內容物,且藉由真空自封閉反應系統移除空氣且用氬氣回填。在三個脫氣循環後,在氬氣下在100℃(油浴)下加熱反應混合物。清空充氣之氬氣氣囊用氬氣再填充,且在反應過程中再安裝。初始淺黃色不均勻反應混合物變成透明雙相灰棕色溶液。在18小時之後,如藉由LC/MS所分析,產物比例無另外變化(62%),使反應混合物冷卻至室溫。在濃縮反應混合物後,將EtOAc/水(200mL/75mL)轉移至濃縮物中,且攪拌30分鐘。分離有機層,且用EtOAc(100mL×2)萃取水層。向經合併之有機層中添加MgSO4(20g)及Celite®(20g),且在攪拌1小時之後對內容物進行抽吸過濾。用EtOAc(300mL)洗滌濾餅,其在真空下藉由旋轉蒸發器濃縮經合併之濾液。將粗濃縮物溶解於1% McOH/CH2Cl2中,且藉由蒸發溶劑接著乾燥來吸附在矽膠(20g)上。藉由乾粉(Combiflash® companion system®,使用RediSep®矽膠管柱120g,30%-70% EtOAc/己烷溶離溶劑)急驟矽膠管柱純化來進行後續純化,在濃縮所需產物溶離份之後得到呈白色結晶固體狀之5-(2-氯吡啶-3-基)-1H-吲唑(1.5g,47%)。1H NMR(DMSO-d6):δ 13.2(s,1H),8.41(dd,J=1.8及4.7Hz,1H),8.13(s,1H),7.90(dd,J=4.7,1.7Hz,1H),7.84(s,1H),7.62(d,J=8.8Hz,1H),7.51(dd,J=7.3,4.7Hz,1H),7.42(dd,J=8.5,1.4Hz,1H)。LCMS:95%,MS(m/e)230(MH+)。
以與製備5-(2-氯吡啶-3-基)-1H-吲唑類似之方式藉由使4-溴喹啉(2.5g,12mmol)、2-氯-3-吡啶酸頻哪醇酯(3.4g,14.4mmol)、Pd(PPh3)4(0.7g,0.60mmol)及2M Na2CO3水溶液(21mL,42mmol)在1,4-二噁烷(100mL)中在100℃下反應來製備4-(2-氯吡啶-3-基)喹啉。1H NMR(300MHz,DMSO-d 6):δ 9.01(d,J=4.4Hz,1H),8.60(dd,J=4.8,1.9Hz,1H),8.13(d,J=8.5Hz,1H),7.98(dd,J=7.5,1.9Hz,1H),7.81(ddd,J=8.4,6.9,1.4Hz,1H),7.64(dd,J=7.5,4.8Hz,1H),7.58(dd,J=6.9,1.3Hz,1H),7.51(d,J=4.4Hz,1H),7.42(dd,J=8.1,1.1Hz,1H)。
以與5-(2-氯吡啶-3-基)-1H-吲唑製備類似之方式自6-溴咪唑并[1,2-a]吡啶-3-甲腈[JMC 54(7),2455-2466,2011](1.5g,6.7mmol)、2-氯-3-吡啶酸頻哪醇酯(1.9g,8.0mmol)、Pd(PPh3)4(0.54g,0.46mmol)及2M Na2CO3水溶液(9.2mL,18.4mmol)在1,4-二噁烷(100mL)中在100℃下隔夜製備6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈。在用CH2Cl2進行萃取處理,接著經MgSO4/Celite®乾燥,及過濾之後,在減壓下濃縮濾液。在EtOAc(25mL)中攪拌所得淺棕色固體,且過濾,得到呈白色固體狀之6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈。1H NMR(300MHz,DMSO-d 6):δ 8.82(d,J=1.9Hz),8.54-8.45(m,2H),8.07(dd,J=7.6,1.9Hz,1H),7.94(d,J=9.3Hz,1H),
7.75(dd,J=9.3,1.7Hz,1H),7.58(dd,J=7.6,4.8Hz,1H)。LCMS:rt 5.34分鐘(B),純度95%,MS(m/e)MH+ 255。
與6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈製備類似地藉由6-溴-[1,2,4]三唑并[1,5-a]吡啶(2.5g,12.5mmol)、2-氯-3-吡啶酸頻哪醇酯(3.6g,15.0mmol)、Pd(PPh3)4(0.58g,0.50mmol)及2M Na2CO3水溶液(17mL,34mmol)在1,4-二噁烷(100mL)中在100℃下之隔夜反應來製備及分離6-(2-氯吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡啶。白色蓬鬆固體(1.76g,61%)。1H NMR(DMSO-d6):δ 9.18(dd,J=1.7,0.8Hz,1H),8.57(s,1H),8.50(dd,J=4.9,2.0Hz,1H),8.05(dd,J=7.6,1.7Hz,1H),7.97(dd,J=9.1,0.9Hz,1H),7.80(dd,J=9.1,1.7Hz,1H),7.57(dd,J=7.6,4.7Hz,1H)。LCMS:rt 4.88分鐘(A),純度95%,MS(m/e)MH+ 231。
以與6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈製備類似之方式藉由7-溴-[1,2,4]三唑并[1,5-a]吡啶(1.0g,5.0mmol)、2-氯-3-吡啶酸頻哪醇酯(3.6g,8.3mmol)、Pd(PPh3)4(0.3g,0.26mmol)及2M Na2CO3水溶液(8mL,16mmol)在1,4-二噁烷(100mL)中在100℃下之隔夜反應來製備及分離7-(2-氯吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡啶。白色蓬鬆固體(0.67g,58%)。1H NMR(300MHz,DMSO-d 6):δ 9.06(d,J=6.5Hz,1H),8.58(s,1H),8.51(dd,J=4.8,1.9Hz,1H),8.03
(dd,J=7.6,1.9Hz,1H),7.99(s,1H),7.58(dd,J=7.6,4.8Hz,1H),7.34(dd,J=7.1,1.8Hz,1H)。LCMS:rt 4.83分鐘(A),純度98%,MS(m/e)MH+ 231。
LCMS:rt 2.15分鐘(A),MS(m/e)314 MH+。
1H NMR(CD3OD,300MHz):8.71(dd,J=5.1,1.8Hz,1H),):8.55(dd,J=7.8,1.5Hz,1H),8.35(s,1H),8.09-8.06(m,2H),7.69-7.62(m,2H),7.51(d,J=8.7Hz,1H),7.40(dd,J=8.7,1.8Hz,1H),7.31(d,J=7.5Hz,1H),7.20(d,J=7.5Hz,1H),2.31(m,3H)。
LCMS:rt 3.43分鐘(A),MS(m/e)318 MH+。
1H NMR(CD3OD,300MHz):8.77(m,1H),8.65(m,1H),8.32(m,1H),8.07-7.94(m,2H),7.76-7.73(m,2H),7.71-7.63(m,2H),7.00(dd,J=8.4,2.7Hz,1H)。
LCMS:rt 1.07分鐘(A),MS(m/e)300 MH+。
1H NMR(CD3OD,300MHz):8.72(m,1H),8.38(m,2H),8.12-
8.06(m,2H),7.85-7.80(m,1H),7.67-7.58(m,2H),7.52-7.49(m,1H),7.44-7.40(m,1H),7.37-7.32(m,1H)。
p-SMAD-3(Ser423/425)SureFire®分析已經設計以量測細胞溶胞物中之內源性細胞p-SMAD-3(Ser423/425)的磷酸化,且為用於篩選受體活化調節劑(例如促效劑及拮抗劑)以及胞內作用劑(諸如上游事件之小分子抑制劑)的系統。分析將量測選殖或內源性受體之p-SMAD-3(Ser423/425),且可應用於初代細胞。
1X溶胞緩衝液:用4ml無菌水稀釋1ml 5×溶胞緩衝液。在稀釋之後,過量1×溶胞緩衝液可經冷凍及解凍高達5次而無活性損失。
活化緩衝液:使緩衝液緩慢升溫至37℃且輕輕地混合以再懸浮。活化緩衝液可儲存在室溫下而無活性損失。
反應緩衝液:緩衝液在使用中保持在4℃下。
AlphaScreen®蛋白質A IgG套組:將套組存放在4℃暗處下。
反應緩衝液+活化緩衝液+AlphaScreen®受體珠粒:將反應緩衝液(40份)、活化緩衝液(10份)及受體珠粒(1份)混合,且將混合物儲存在室溫下且在當天使用。向384孔培養盤中添加混合物;棄去過量混合物。
稀釋緩衝液+AlphaScreen®供體珠粒:將稀釋緩衝液(20份)及供體珠粒(1份)混合,且將混合物儲存在室溫下且在當天使用。棄去過量混合物。
分析對照樣本:在於250μl水中復原之後,溶胞物於-20℃下分成單次使用等分試樣。
用於293FT及RMS13黏附細胞之96孔分析方案可手動進行或用液體處理機器人以高通量進行。
將細胞(96孔培養盤80μL細胞)塗覆在經膠原蛋白塗佈之組織培養培養盤中的RPMI或FreeStyle培養基(Invitrogen)中且培育隔夜。對於手動分析,GDF8使用6個培養盤,TGFβ使用6個培養盤,且Alk5ca(ALK5組成性活性)視情況使用6個培養盤。
如下製備化合物稀釋培養盤:將12μL DMSO轉移至96孔培養盤之第一行中,且將16μL DMSO轉移至96孔培養盤中之第2-12行中。將12μL化合物溶液轉移至含DMSO之96孔培養盤的第一行中。進行三倍稀釋直至第10行含DMSO之96孔培養盤。
用化合物處理含有細胞之培養盤持續約10分鐘,且隨後添加配位體。向培養盤中添加GDF8或TGFb以進行刺激。在37℃下刺激293FL細胞90分鐘;且在37℃下刺激RMS13細胞60分鐘。隨後自細胞移除培養基,且添加1×溶胞緩衝液(約25μL),且將培養盤在培養盤震盪器上輕輕攪動5-10分鐘。
隨後將溶胞物(5μL)置放至384孔淺培養盤中,避免產生氣泡。向其中添加反應緩衝液+活化緩衝液+AlphaScreen®受體珠粒混合物(5μL)。用黏附性覆蓋層密封培養盤,並且防護遮受(例如,用金屬箔),且在室溫下在培養盤震盪器上輕輕攪動2小時。
隨後添加稀釋緩衝液+AlphaScreen®供體珠粒(2μL),且將培養盤插在培養盤震盪器上再持續1½小時。在完成之後,使用AlphaScreen® pSMAD3®設定在Synergy-4或Enspire培養盤讀取器上讀取培養盤。
TGF-β(資料=TGF-β pSMAD(MPC-11)(μM))及GDF8(資料=GDF pSMAD(MPC11)(μM))信號傳導抑制之代表性結果展示於表1
中:
對以下化合物中之每一者報導的分析型LC-MS/HPLC滯留時間使用以下通用分析型LC-MS/HPLC條件中之一者來產生:
A:管柱:Waters Acquity UPLC BEH C18(2.1×50mm),1.7μ;移動相A:含0.1% TFA之水;移動相B:含0.1% TFA之乙腈;梯度=經1.1分鐘20%-90% B,隨後在90% B下保持0.6分鐘;溫度:50℃;流動速率:0.7mL/min;偵測:220nm處之UV。
B:管柱:Waters Acquity UPLC BEH C18(2.1×50mm)1.7μ,移動相A:10mM NH4OAc,乙腈(95:5);移動相B:10mM NH4OAc:乙腈(5:95),梯度=經1.1分鐘20%-90% B,隨後在90% B下保持0.6分鐘;溫度:50℃;流動速率:0.7mL/min;偵測:220nm處之UV。
C:管柱:Ascentis Express C18(2.1×50mm),2.7μ;移動相A:10mM NH4OAc,乙腈(95:5);移動相B:10mM NH4OAc:乙腈(5:95),梯度=經3分鐘0%-100% B;溫度:50℃;流動速率:1.1mL/min;偵測:220nm處之UV。
D:管柱:Ascentis Express C18(50×2.1)mm,2.7μ;移動相A:0.1% TFA:乙腈(95:5),移動相B:0.1% TFA:乙腈(5:95),梯度=經3分鐘0%-100% B;溫度:50℃;流動速率:1.1mL/min;偵測:220nm處之UV。
E:管柱:Kinetex XB-C18(75×3mm)2.6μ;移動相A:10mM
甲酸銨:乙腈(98:2),移動相B:10mM甲酸銨:乙腈(2:98),梯度=經4分鐘20%-100% B,隨後在100% B下保持0.6分鐘;溫度:27℃;流動速率:1.0mL/min;偵測:220nm處之UV。
F:管柱:Waters X-Bridge C18,19×150mm,5μ;移動相A:含0.1% TFA之水;移動相B:乙腈;梯度:經25分鐘10%-100% B,隨後在100% B下保持5分鐘;流速:15mL/min。
G:管柱:Inertsil ODS,250×20mm ID,5μ;移動相A:含0.1% TFA之水;移動相B:乙腈;梯度:經25分鐘10%-100% B,隨後在100% B下保持5分鐘;流速:17mL/min。
H:管柱:Inertsil ODS,250×20mm ID,5μ;移動相A:含10mM NH4OAc之水;移動相B:甲醇;梯度:經25分鐘10%-100% B,隨後在100% B下保持5分鐘;流速:17mL/min。
I:管柱:DAD-1 X-Bridge phenyl,150×4.6mm 5μ;DAD-2 Sunfire C18,150×4.6mm 5μ;移動相A:含10mM NH4OAc之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:1mL/min。
J:管柱:Sunfire C18,150×4.6mm,5μ;移動相A:含0.05% TFA之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:1mL/min。
K:管柱:Inertsil ODS,150×4.6mm,5μ;移動相A:含10mM NH4OAc之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:17mL/min。
L:管柱:Sunfire C18,150×19mm ID,5μ;移動相A:含10mM NH4OAc之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:17mL/min。
M:管柱:Synergy Polar,250×21.2 ID,4μ;移動相A:含0.1% TFA之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:17mL/min。
N:管柱:Waters X-Bridge C18,19×150mm,5μ;移動相A:含10mM NH4OAc之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:17mL/min。
O:管柱:Symmetry C8,300×19mm ID,7μ;移動相A:含10mM NH4OAc之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:17mL/min。
P:管柱:X-Bridge Phenyl,250×19mm ID,5μ;移動相A:含10mM NH4OAc之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:17mL/min。
Q:管柱:DAD1-X-Bridge Phenyl,4.6×250mm,5μ;DAD2-X-Terra RP18,4.6×250mm,5μ;移動相A:含0.05% TFA之水;移動相B:乙腈;梯度:經18分鐘0%-100% B,隨後在100% B下保持5分鐘;流速:2mL/min。
向化合物1A(參考文獻:WO 2015157093 A1及WO2014055955 A1)(200mg,0.785mmol)於1,4-二噁烷(10mL)中之溶液中添加2-(三丁基錫烷基)吡啶(318mg,0.864mmol)。用氬氣使反應混合物脫氣。隨後,添加Pd(PPh3)4(91mg,0.079mmol),且再次使反應混合物脫
氣,且在110℃下攪拌36小時。隨後使其冷卻至室溫,且在減壓下移除揮發物,得到棕色固體。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈13(205mg,0.690mmol,產率88%)。LCMS:m/z=298.1[M+H]+;滯留時間0.99分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.78(dd,J=1.6,4.8Hz,1H),8.59(dd,J=1.2,1.6Hz,1H),8.46(s,1H),8.30-8.31(m,1H),8.11(dd,J=1.6,7.6Hz,1H),7.90-7.92(m,2H),7.62-7.68(m,2H),7.33-7.34(m,1H),7.16(dd,J=2.0,9.6Hz,1H)。
向化合物1A(200mg,0.785mmol)及2-溴-6-(三氟甲基)吡啶(195mg,0.864mmol)於1,4-二噁烷(2mL)中之攪拌溶液中添加六甲基二錫(0.326mL,1.571mmol),且用氮氣吹掃反應混合物5分鐘。隨後添加Pd(PPh3)4(0.091g,0.079mmol),且再次吹掃混合物10分鐘。隨後將其在110℃下加熱16小時。經由針筒過濾器過濾反應混合物,且濃縮濾液。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈黃色固體狀之6-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈14(0.15g,0.411mmol,產率52.3%)。LCMS:m/z=366.1[M+H]+;滯留時間1.67分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.81-8.85(m,1 H)8.58-8.62(m,1 H)8.44-8.48(m,1 H)8.29-8.36(m,1 H)8.17-8.24(m,1 H)8.08-8.13(m,1 H)7.78-7.83(m,1 H)7.66-
7.72(m,2 H)7.22-7.28(m,1 H)。
向化合物1A(50mg,0.196mmol)及6-溴-3-氟-2-甲基吡啶(37.3mg,0.196mmol)於1,4-二噁烷(2mL)中之溶液中添加六甲基二錫(0.041mL,0.196mmol)。用氬氣使溶液脫氣,且隨後添加Pd(PPh3)4(22.69mg,0.020mmol)。在CEM微波儀器中將反應混合物在140℃下攪拌1小時。使反應混合物冷卻,過濾且在減壓下蒸發濾液。藉由製備型HPLC(方法N)來純化粗殘餘物,得到6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈15(15.9mg,0.047mmol,產率24.1%)。LCMS:m/z=330.1[M+H]+;滯留時間1.28分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.76(dd,J=4.6,1.7Hz,1H),8.58(dd,J=1.7,1.0Hz,1H),8.48-8.44(m,1H),8.07(dd,J=7.7,1.6Hz,1H),7.80(dd,J=8.6,3.7Hz,1H),7.73-7.65(m,2H),7.61(dd,J=7.8,4.6Hz,1H),7.23(dd,J=9.3,1.7Hz,1H),2.07(d,J=2.9Hz,3H)。
向2-溴-4-氟吡啶(0.3g,1.71mmol)於1,4-二噁烷(5mL)中之攪拌
溶液中添加六甲基二錫(0.43mL,2.1mmol)。用N2吹掃反應混合物10分鐘,且向其中添加Pd(Ph3P)4(0.20g,0.17mmol)。用N2再次吹掃反應混合物再10分鐘,且在110℃下加熱2小時。隨後,在冷卻至室溫之後,添加化合物1A(0.43g,1.71mmol),且用N2吹掃混合物5分鐘,接著添加Pd(Ph3P)4(0.2g,0.17mmol)。將反應物再次在110℃下加熱18小時。在真空下濃縮反應混合物,得到粗殘餘物,其藉由製備型HPLC(條件N)來純化,得到6-(4'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈16(0.38mg,0.89mmol,產率52.3%)。LC-MS:m/z=317.1[M+H]+;滯留時間1.41分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.93-8.89(m,1H),8.60-8.57(m,1H),8.27-8.19(m,3H),8.03-7.97(m,1H),7.77-7.72(m,1H),7.42-7.37(m,1H),7.34-7.27(m,1H)。
向化合物1A(0.2g,0.79mmol)及2-甲氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶1B(0.24g,1.02mmol)於1,4-二噁烷(10mL)/H2O(2mL)中之攪拌溶液中添加K3PO4(0.5g,2.36mmol)。使反應混合物脫氣3分鐘,且隨後向其中添加PdCl2(dppf)-CH2Cl2加合物(0.032g,0.039mmol),且將所得混合物在100℃下加熱12小時。隨後經由Celite®墊過濾反應混合物,用乙酸乙酯洗滌濾餅,且在減壓下
蒸發經合併之濾液,得到粗化合物,其藉由製備型HPLC(條件N)來純化,得到6-(6'-甲氧基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈17(0.2mg,0.054mmol,產率68.5%)。LCMS:m/z=328.1[M+H]+;滯留時間1.49分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.78(dd,J=4.6,1.7Hz,1H),8.63(dd,J=1.7,1.0Hz,1H),8.48(s,1H),8.07(dd,J=7.7,1.6Hz,1H),7.86-7.70(m,2H),7.66-7.55(m,2H),7.25(dd,J=9.2,1.8Hz,1H),6.79-6.66(m,1H),3.04(s,3H)。
在室溫下向H2SO4(0.066mL,1.232mmol)於TFA(0.274mL,3.56mmol)中之攪拌溶液中添加化合物14,且攪拌所得混合物10分鐘。隨後將其在85℃下加熱2小時。此後,添加冰冷水(5mL),且用10% NaOH水溶液使溶液鹼化。過濾沈澱固體,且藉由製備型HPLC(條件H)來純化,得到呈灰白色固體狀之6-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺18(50mg,0.130mmol,產率47.6%)。LCMS:m/z=384.0[M+H]+;滯留時間1.82分鐘;條件E。1H NMR(400MHz,DMSO-d6)δ ppm 9.32-9.36(m,1 H)8.80-8.84(m,1 H)8.31-8.34(m,1 H)8.22-8.27(m,2 H)8.15-8.21(m,1 H)8.04-8.09(m,1 H)7.76-7.81(m,1 H)7.63-7.71(m,1 H)7.54-7.59(m,1 H)7.10-7.17(m,2 H)。
在25mL圓底燒瓶中添加含15(140mg,0.425mmol)及K2CO3(176mg,1.275mmol)之DMSO(2mL)。使混合物冷卻至0℃,且逐滴添加H2O2(0.977mL,12.75mmol,30% v/v)。使反應混合物達到室溫,且再攪拌3小時。隨後用冰水稀釋反應混合物,且過濾所獲得之固體,用水洗滌,且乾燥,得到呈灰白色固體狀之6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺19(73mg,0.205mmol,產率48.2%)。LCMS:m/z 348.2[M+H]+;滯留時間1.34分鐘;條件E。1H NMR(400MHz,DMSO-d6)δ ppm 9.37(dd,J=2.0,1.0Hz,1H),8.74(dd,J=4.8,1.8Hz,1H),8.35-8.31(m,1H),8.01-7.87(m,2H),7.76-7.69(m,1H),7.69-7.55(m,3H),7.35(br.s.,1H),7.16-7.10(m,1H),2.07(d,J=3.0Hz,3H)。
藉由使1A及6-溴-3-氟吡啶反應且採用流程3(方法C)中所描述之實驗程序來合成化合物20。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈20(14
mg,0.044mmol,產率34.7%)。LCMS:m/z=316.1[M+H]+;滯留時間1.49分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.76(dd,J=4.6,1.7Hz,1H),8.60(dd,J=1.7,1.0Hz,1H),8.45(s,1H),8.30(s,1H),8.13-8.07(m,1H),8.03-7.95(m,1H),7.87-7.78(m,1H),7.70-7.56(m,2H),7.15(dd,J=9.3,2.0Hz,1H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自20合成化合物21。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺21(57.3mg,0.172mmol,產率24.8%)。LCMS m/z=334.1[M+H]+;滯留時間0.98分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.39(dd,J=1.8,0.9Hz,1H),8.77-8.72(m,1H),8.34-8.26(m,2H),8.03(d,J=1.7Hz,1H),7.94(d,J=0.5Hz,2H),7.82(td,J=8.7,2.9Hz,1H),7.65-7.59(m,1H),7.54(s,1H),7.37(d,J=7.3Hz,1H),7.08(d,J=2.0Hz,1H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自16合成化合物22。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(4'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺22(3.9mg,0.012mmol,產率0.96%)。LCMS:m/z=334.1[M+H]+;滯留時間
0.86分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.40(dd,J=2.0,1.0Hz,1H),8.77(dd,J=4.8,1.6Hz,1H),8.34-8.22(m,2H),8.05(d,J=1.7Hz,1H),7.94(d,J=4.4Hz,1H),7.78(d,J=2.7Hz,1H),7.66(d,J=4.6Hz,1H),7.55(dd,J=9.3,1.0Hz,1H),7.38(br.s.,1H),7.26(ddd,J=8.9,5.7,2.4Hz,1H),7.11(dd,J=9.3,2.0Hz,1H)。
採用流程4(方法D)中所描述之實驗程序藉由使1A及6-溴-2-(二氟甲基)-3-氟吡啶反應來合成化合物23。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(6'-(二氟甲基)-5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈23(250mg,0.438mmol,產率33%)。LCMS:m/z=366.1[M+H]+;滯留時間1.62分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.79(dd,J=4.8,1.6Hz,1H),8.60(d,J=1.0Hz,1H),8.45(s,1H),8.24(dd,J=8.9,3.8Hz,1H),8.12-8.06(m,1H),8.05-7.97(m,1H),7.69-7.57(m,2H),7.21(dd,J=9.3,1.7Hz,1H),6.85-6.55(m,1H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自23
合成化合物24。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(6'-(二氟甲基)-5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺24(37.6mg,0.098mmol,產率25.6%)。LCMS m/z=384.1[M+H]+;滯留時間1.24分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.66-9.58(m,1H),9.06(d,J=1.5Hz,1H),8.59(s,1H),8.40(d,J=3.9Hz,1H),8.33-8.22(m,2H),8.20-8.09(m,1H),7.93(d,J=7.8Hz,1H),7.83(dd,J=9.3,0.7Hz,1H),7.66-7.55(m,1H),7.41(dd,J=9.2,1.8Hz,1H),7.13-6.96(m,1H)。
採用流程4(方法D)中所描述之實驗程序藉由使1A及6-溴菸鹼酸甲酯反應來合成化合物25。藉由製備型HPLC(條件N)來純化粗殘餘物,得到3'-(3-氰基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-5-甲酸甲酯25(150mg,0.35mmol,產率25.2%)。LCMS m/z=356.2[M+H]+;滯留時間1.14分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ 8.81(dd,J=4.5,1.5Hz,1H),8.78-8.73(m,1H),8.68-8.62(m,1H),8.47(s,1H),8.40(dd,J=8.3,2.3Hz,1H),8.198.13(m,1H),8.11-8.06(m,1H),7.71-7.62(m,2H),7.19-7.12(m,1H),3.86(s,3H)。
當採用類似於如流程7(方法B)中所描述之19合成的實驗程序時,自25獲得化合物26及27。藉由製備型HPLC(條件N)來純化粗殘餘物,得到3'-(3-胺甲醯基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-5-甲酸甲酯26(4mg,10.71μmol,產率3.8%)及3'-(3-胺甲醯基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-5-甲酸27(20.1mg,0.056mmol,產率19.9%)。對26之分析:LCMS:m/z=374.1[M+H]+;滯留時間0.88分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.70-9.67(m,1H),9.08-9.02(m,2H),8.66-8.62(m,1H),8.60(s,1H),8.36-8.27(m,2H),8.25-8.19(m,1H),7.94(dd,J=7.8,4.6Hz,1H),7.82(s,1H),7.65(br.s.,1H),7.33(dd,J=9.0,1.7Hz,1H),4.12(s,3H)。對27之分析:LCMS m/z=360.1[M+H]+;滯留時間0.57分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 13.68(br.s.,1H),9.72-9.64(m,1H),9.09-8.97(m,2H),8.62(d,J=2.2Hz,2H),8.35-8.18(m,3H),7.93(dd,J=7.7,4.8Hz,1H),7.81(d,J=9.0Hz,1H),7.66(br.s.,1H),7.32(dd,J=9.2,1.8Hz,1H)。
採用流程4(方法D)中所描述之實驗程序藉由使1A及2-溴-6-(二氟
甲基)吡啶反應來合成化合物28。藉由製備型HPLC(方法N)來純化粗殘餘物,得到呈黃色固體狀之6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈28(0.22g,0.633mmol,產率81%)。LCMS:m/z=348.1[M+H]+;滯留時間1.35分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.79-8.83(m,1 H)8.53-8.57(m,1 H)8.41-8.47(m,1 H)8.07-8.13(m,3 H)7.56-7.72(m,3 H)7.18-7.24(m,1 H)6.33-6.66(m,1 H)。
以類似於18之方式採用流程6(方法A)中所描述之實驗程序自28合成化合物29。藉由製備型HPLC(條件H)來純化粗殘餘物,得到呈灰白色固體狀之6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺29(45mg,0.123mmol,產率28.5%)。LCMS m/z=366.2[M+H]+;滯留時間1.58分鐘;條件E。1H NMR(400MHz,DMSO-d6)δ ppm 9.36-9.43(m,1 H)8.76-8.82(m,1 H)8.32(s,1 H)7.98-8.11(m,3 H)7.8(s,1H)7.63-7.70(m,1 H)7.51-7.62(m,2 H)7.4(s,1H)7.09-7.15(m,1 H)6.36-6.69(m,1 H)。
採用流程4(方法D)中所描述之實驗程序藉由使1A及2-溴-6-乙基
吡啶反應來合成化合物30。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(6'-乙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈30(2.4mg,產率1%)。LCMS m/z=326.1[M+H]+;滯留時間1.46分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.02-9.05(m,1 H)8.75-8.78(m,1 H)8.70-8.72(m,1 H)8.31-8.36(m,1 H)8.04-8.08(m,2 H)7.94-7.99(m,1 H)7.85-7.90(m,1 H)7.49-7.52(m,1 H)7.41-7.44(m,1 H)2.57-2.66(m,2 H)0.76-0.83(m,3 H)。
採用流程2(方法B)中所描述之實驗程序藉由使1A及2-溴-6-異丙基吡啶反應來合成化合物31。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-異丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈31(150mg,4.4mmol,產率45%)。LCMS:m/z=340.1[M+H]+;滯留時間1.58分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.76-8.80(m,1H),8.43-8.50(m,2H),8.05-8.11(m,1H),7.83-7.88(m,2H),7.70-7.75(m,1H),7.59-7.66(m,1H),7.26(dd,J=1.76,9.29Hz,1H),7.19(dd,J=2.76,5.77Hz,1H),2.68(td,J=1.63,3.76Hz,1H),0.64(d,J=7.03Hz,6H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自31合成化合物32。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-異丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺32(59.7mg,0.164mmol,產率55.6%)。LCMS:m/z=358.2[M+H]+;滯留時間1.15分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.40(d,J=6.85Hz,6H),7.44-7.36(m,1H),2.96-2.87(m,2H),2.49-2.38(m,2H),2.28-2.18(m,2H),2.03(dd,J=1.59,7.70Hz,1H),1.71(s,1H),1.26(dd,J=1.71,4.65Hz,1H),0.69(dd,J=0.98,1.71Hz,1H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自17合成化合物33。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-甲氧基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺33(53mg,0.150mmol,產率24.6%)。LCMS:m/z=346.1[M+H]+;滯留時間1.06分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.42(dd,J=1.8,0.9Hz,1H),8.78-8.70(m,1H),8.34(s,1H),8.00-7.71(m,3H),7.63-7.52(m,3H),7.34(br.s.,1H),7.15(dd,J=9.2,1.8Hz,1H),6.70(dd,J=8.3,0.7Hz,1H),3.03(s,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使1A及2-溴-6-環丙基吡啶反應來合成化合物34。藉由製備型HPLC(條件F)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-環丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈34(100mg,2.96mmol,產率30.2%)。LCMS:m/z=338.1[M+H]+;滯留時間1.65分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.76(dd,J=4.9,1.5Hz,1H),8.54(s,1H),8.48(s,1H),8.04(dd,J=7.7,1.6Hz,1H),7.78-7.74(m,2H),7.71(d,J=9.3Hz,1H),7.60(dd,J=7.8,4.6Hz,1H),7.27-7.22(m,1H),7.16(dd,J=9.3,1.7Hz,1H),1.82(ddd,J=12.5,8.3,4.6Hz,1H),0.48-0.41(m,2H),0.03-0.08(m,2H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自34合成化合物35。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-環丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺35(16.3mg,0.045mmol,產率30.6%)。LCMS:m/z=356.1[M+H]+;滯留時間1.29分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.61(d,J=0.7Hz,1H),9.00(dd,J=4.8,1.6Hz,1H),8.61(s,1H),8.21(dd,J=7.7,1.6Hz,2H),8.06-7.92(m,2H),7.90-7.75(m,2H),
7.60(br.s.,1H),7.53-7.41(m,1H),7.29(dd,J=9.3,1.7Hz,1H),2.13-1.94(m,1H),0.72-0.56(m,2H),0.22-0.13(m,2H)。
採用流程4(方法D)中所描述之實驗程序藉由使1A及6-溴-2-氟吡啶反應來合成化合物36。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈36(130mg,4.12mmol,產率52.4%)。LCMS:m/z=316.1[M+H]+;滯留時間1.35分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.06(dd,J=4.8,1.6Hz,1H),8.92(s,1H),8.75(s,1H),8.42-8.29(m,2H),8.11(dd,J=7.6,2.2Hz,1H),7.98(d,J=9.3Hz,1H),7.92(dd,J=7.8,4.9Hz,1H),7.48(dd,J=9.3,1.7Hz,1H),7.41(dd,J=7.9,2.6Hz,1H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自36合成化合物37。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺37(13.5mg,0.040mmol,產率12.6%)。LCMS:m/z=334.1[M+H]+;滯留時間1.06分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.39(dd,J=0.98,1.96Hz,1H),8.77(dd,J=1.59,4.77Hz,1H),8.34(s,1H),8.01-8.09(m,2H),7.89-7.99(m,1H),7.77(dd,J=2.32,
7.21Hz,1H),7.56-7.68(m,2H),7.36(br.s.,1H),7.06-7.15(m,2H)。
採用流程2(方法B)中所描述之實驗程序藉由使1A及2-(苯甲氧基)-6-溴吡啶反應來合成化合物38。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(6'-(苯甲氧基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈38(24.1mg,0.06mmol,15.21%)。LCMS m/z=404.1[M+H]+;滯留時間1.97;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.78(dd,J=4.9,1.7Hz,1H),8.66(dd,J=1.7,1.0Hz,1H),8.50(s,1H),8.07(dd,J=7.7,1.6Hz,1H),7.86(dd,J=8.1,7.3Hz,1H),7.71-7.79(m,2H),7.60-7.63(m,1H),7.29-7.20(m,4H),6.95-6.87(m,2H),6.81(dd,J=8.3,0.7Hz,1H),4.31(s,2H)。
以類似於18之方式採用流程6(方法A)中所描述之實驗程序自13合成化合物39。藉由製備型HPLC(條件H)來純化粗化合物,得到6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺39(14.3g,0.045mmol,產率13.3%)。LCMS:m/z=316.2[M+H]+;滯留時間1.22分鐘;條件B。1H NMR(400MHz,DMSO-d6)δ ppm 9.40(d,J=0.8Hz,1H),8.75(dd,J=1.6,4.8Hz,1H),8.32(s,1H),8.27(d,J=4.4Hz,1H),8.01(dd,J=1.6,7.6Hz,1H),7.95(bs,1H),7.83-7.90(m,2H),
7.61(dd,J=4.8,8.0Hz,1H),7.52(d,J=9.2Hz,1H),7.35(bs,1H),7.28-7.31(m,1H),7.03(dd,J=2.0,9.2Hz,1H)
採用流程2(方法B)中所描述之實驗程序藉由使1A及1-(6-溴吡啶-2-基)乙酮反應來合成化合物40。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(6'-乙醯基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈40(6.5mg,0.019mmol,4.9%)。LCMS:m/z=340.1[M+H]+;滯留時間1.38;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.83(dd,J=4.6,1.7Hz,1H),8.73(dd,J=1.7,1.0Hz,1H),8.47(s,1H),8.33(dd,J=7.8,1.0Hz,1H),8.16-8.10(m,2H),7.86(dd,J=7.7,1.1Hz,1H),7.73-7.65(m,2H),7.24(dd,J=9.3,1.7Hz,1H),1.72(s,3H)。
在0℃下向化合物40(0.09g,0.265mmol)於THF(5mL)中之溶液中添加甲基溴化鎂(0.086mL,0.292mmol)之3.4M溶液,且攪拌反應2小時。隨後用飽和NH4Cl水溶液淬滅,且用乙酸乙酯(2×50mL)萃取。用水、鹽水洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且
在減壓下濃縮濾液,得到粗殘餘物。其藉由製備型HPLC(條件N)來進行純化,得到6-(6'-(2-羥基丙-2-基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈41(7.1mg,0.020mmol,產率7.46%)。LCMS:m/z=356.1[M+H]+;滯留時間1.05;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.77(s,1H),8.51-8.51(m,1H),8.48(dd,J=0.92,1.59Hz,1H),8.05(d,J=7.76Hz,1H),7.84-7.94(m,2H),7.74-7.77(m,1H),7.50-7.64(m,2H),7.22-7.25(m,1H),1.81(s,1H),0.76(s,6H)。
採用流程4(方法D)中所描述之實驗程序藉由使1A及2-溴-4,6-二甲基吡啶反應,且隨後類似於19採用流程7(方法B)中所描述之實驗程序使所得氰基化合物水解,來合成化合物42。藉由製備型HPLC(條件P)來純化粗殘餘物,得到6-(4',6'-二甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺42(42.6mg,0.122mmol,產率39.6%)。LCMS:m/z=344.2[M+H]+;滯留時間1.56分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.39(d,J=0.7Hz,1H),8.73(dd,J=4.6,1.5Hz,1H),8.32(s,1H),7.96(dd,J=7.7,1.6Hz,2H),7.58(dd,J=7.7,4.8Hz,1H),7.55-7.49(m,2H),7.37(br.s.,1H),7.12-7.06(m,1H),6.96(s,1H),2.29(s,3H),2.02(s,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使1A及N-(6-溴吡啶-2-基)甲磺醯胺[參考文獻:WO2011141848 A1/Organic & Biomolecular Chemistry(2015),13(25),7050-7066]反應來合成化合物44。藉由製備型HPLC(方法:N)來純化粗殘餘物,得到呈黃色固體狀之N-(3'-(3-氰基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-6-基)甲磺醯胺44(0.07g,0.179mmol,產率22.8%)。LCMS:m/z=391.1[M+H]+;滯留時間1.03分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 10.31(s,1H)8.68-8.89(m,1 H)8.55-8.58(m,1 H)8.41-8.44(m,1 H)8.08-8.14(m,1 H)7.82-7.89(m,1 H)7.60-7.67(m,2 H)7.55-7.59(m,1 H)7.07-7.13(m,1 H)6.87-6.92(m,1 H)2.72-2.76(m,3 H)。
採用流程1(方法A)中所描述之實驗程序藉由使1A及2-氯-6-(三丁基錫烷基)吡啶反應來合成化合物3AA。藉由矽膠層析(40g RediSep®
管柱,用20%-30%乙酸乙酯/石油醚之梯度溶離)來純化粗殘餘物,得到呈無色液體狀之6-(6'-氯-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈3AA(0.25g,0.460mmol,產率29.3%)。LCMS:m/z=332.2[M+H]+;滯留時間2.46分鐘;條件E。
向6-(6'-氯-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈3AA(100mg,0.301mmol)、乙醯胺(26.7mg,0.452mmol)、4,5-雙(二苯膦基)-9,9-二甲基二苯并哌喃乙醯胺(34.9mg,0.060mmol)及Cs2CO3(196mg,0.603mmol)於1,4-二噁烷(10mL)中之攪拌溶液中添加參(二苯亞甲基丙酮)二鈀(0)(27.6mg,0.030mmol)。將反應混合物在100℃下加熱12小時。使混合物冷卻至室溫,且經由Celite®墊過濾,用乙酸乙酯洗滌濾餅,且在減壓下蒸發經合併之濾液,得到粗化合物,其藉由製備型HPLC(條件N)來純化,得到N-(3'-(3-氰基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-6-基)乙醯胺45(17.4mg,0.048mmol,產率15.8%)。LCMS:m/z=355.1[M+H]+;滯留時間1.22分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 10.14(s,1H),8.76(d,J=4.5Hz,1H),8.66-8.57(m,1H),8.46(s,1H),8.15(d,J=9.5Hz,1H),8.01(d,J=8.0Hz,1H),7.79(d,J=15.6Hz,1H),7.67-7.50(m,2H),7.35(d,J=7.5Hz,1H),7.12-6.94(m,1H),1.95(s,3H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自3AJ合成化合物46。藉由製備型HPLC(條件H)來純化粗殘餘物,得到6-(6'-氯-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺46(7.3mg,0.020mmol,產率5.6%)。LCMS:m/z=350.1[M+H]+;滯留時間1.13分鐘;條件C。1H NMR 1H NMR(400MHz,DMSO-d6)δ 9.38(d,J=0.7Hz,1H),8.77(dd,J=4.6,1.5Hz,1H),8.33(s,1H),8.05-7.97(m,1H),7.95-7.86(m,2H),7.85-7.80(m,1H),7.67-7.61(m,2H),7.58(s,1H),7.42(dd,J=7.8,0.7Hz,1H),7.12(dd,J=9.2,1.8Hz,1H)。
以類似於化合物13之方式採用流程1(方法A)中所描述之實驗程序藉由使3AD(參考文獻:WO 2015157093 A1/WO 2014055955 A1)及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物47。藉由製備型HPLC(方法:I)來純化粗殘餘物,得到6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶47(17mg,0.069mmol,產率15.80%)。LCMS:m/z=287.1[M+H]+;滯留時間1.16分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.72(dd,J=4.6,1.5Hz,1H),8.53(s,1H),7.97(dd,
J=7.6,1.5Hz,1H),7.89(s,1H),7.75-7.69(m,1H),7.60-7.53(m,3H),7.36(d,J=9.3Hz,1H),7.15(d,J=7.6Hz,1H),6.78(dd,J=9.3,1.7Hz,1H),2.13(s,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使3AD及6-溴-2-(二氟甲基)-3-氟吡啶反應來合成化合物48。藉由製備型HPLC(方法I)來純化粗殘餘物,得到6-(6'-(二氟甲基)-5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶48(6.8mg,0.020mmol,產率3.3%)。LCMS:m/z=341.1[M+H]+;滯留時間1.43分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ=8.76(dd,J=4.6,1.5Hz,1H),8.56(s,1H),8.10(dd,J=8.7,3.8Hz,1H),8.05-7.99(m,2H),7.89(s,1H),7.64(dd,J=7.7,4.8Hz,1H),7.56(s,1H),7.42-7.34(m,1H),6.92-6.56(m,2H)。
採用流程4(方法D)中所描述之實驗程序藉由使4(參考文獻:WO
2015157093 A1及WO 2014055955 A1)及2-溴-6-(二氟甲基)吡啶反應來合成化合物49。藉由製備型HPLC(條件H)來純化粗殘餘物,得到6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈49(242mg,0.0604mmol,產率62.9%)。LCMS:m/z=349.1[M+H]+;滯留時間1.53分鐘,條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.92(dd,J=4.6,1.7Hz,1H),8.36(dd,J=8.1,1.0Hz,1H),8.25(d,J=9.3Hz,1H),8.21-8.18(m,2H),8.16(t,J=7.8Hz,1H),7.74(dd,J=7.7,4.8Hz,1H),7.61(d,J=7.8Hz,1H),7.43(d,J=9.5Hz,1H),6.26(s,1H)。
採用流程5(方法E)中所描述之實驗程序藉由使4及2-甲氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶反應來合成化合物50。藉由製備型HPLC(條件L)來純化粗產物,得到6-(6'-甲氧基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈50(125mg,0.35mmol,產率44.8%)。LCMS:m/z=329.2[M+1]+;滯留時間1.54分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.48(dd,J=4.8,1.6Hz,1H),8.21(s,1H),7.89(d,J=9.5Hz,2H),7.77-7.63(m,1H),7.45(d,J=5.9Hz,1H),7.33-7.21(m,1H),6.98(d,J=9.3Hz,1H),6.42-6.19(m,1H),2.91(s,3H)。
自50且採用流程6(方法A)中所描述之實驗程序來合成化合物51。藉由製備型HPLC條件L)來純化粗殘餘物,得到化合物51(28.9mg,0.083mmol,產率27.1%)。LCMS:m/z=347.2[M+H]+;滯留時間1.02分鐘;條件E。1H NMR(400MHz,DMSO-d6)δ ppm 8.88-8.82(m,1H),8.29-8.19(m,3H),7.89-7.82(m,1H),7.79-7.73(m,2H),7.70-7.65(m,1H),7.63-7.59(m,1H),7.37(s,1H),6.77-6.71(m,1H),2.89(s,3H).
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自5合成化合物52。藉由製備型HPLC(條件H)來純化粗殘餘物,得到6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺52(38.7mg,0.105mmol,產率36.4%)。LCMS:m/z=367.2[M+H]+;滯留時間1.18分鐘;條件E。1H NMR(400MHz,DMSO-d6)δ ppm 8.91(dd,J=4.8,1.8Hz,1H),8.32-8.21(m,4H),8.15(s,1H),7.75(dd,J=7.8,4.8Hz,1H),7.70-7.65(m,1H),7.62(s,1H),7.49-7.44(m,1H),7.39(d,J=9.5Hz,1H),6.39(s,1H)。
採用流程4(方法D)中所描述之實驗程序藉由使4及2-溴-5-氟吡啶反應來合成化合物53。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈53(220mg,0.58mmol,產率34.3%)。LCMS=m/z 317.1[M+H]+;滯留時間1.24分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.89(dd,J=4.8,1.8Hz,1H),8.60(s,1H),8.27-8.22(m,3H),8.20-8.16(m,1H),7.94-7.87(m,1H),7.71(dd,J=7.8,4.8Hz,1H),7.33(d,J=9.5Hz,1H)。
採用流程6(方法A)中所描述之實驗程序自53合成化合物54。製備型HPLC(條件M)來純化粗殘餘物,得到6-(5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺54(10.3mg,0.031mmol,產率6.4%)。LCMS:m/z=335.1[M+H]+;滯留時間0.77分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.86(dd,J=4.8,1.6Hz,1H),8.26(s,3H),8.22-8.18(m,1H),8.17-8.12(m,1H),7.87(td,J=8.8,2.9Hz,1H),7.79(br.s.,1H),7.70(dd,J=7.8,4.9Hz,1H),7.57(br.s.,1H),7.30-7.26(m,1H)。
採用流程4(方法D)中所描述之實驗程序藉由使4及2-溴-5-甲基吡啶反應來合成化合物55。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(5'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈55(65mg,0.2mmol,產率21.5%)。LCMS:m/z=313.1[M+H]+;滯留時間1.42分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.88(dd,J=4.9,1.7Hz,1H),8.59(s,1H),8.20(s,1H),8.16-8.09(m,2H),8.05-8.03(m,1H),7.81-7.77(m,1H),7.70-7.65(m,1H),7.25(d,J=9.5Hz,1H),2.27(s,3H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自55合成化合物56。藉由製備型HPLC(條件H)來純化粗殘餘物,得到6-(5'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺56(12mg,0.036mmol,產率28.4%)。LCMS:m/z=331.1[M+H]+;滯留時間1.04分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.86(dd,J=5.0,1.5Hz,1H),8.28(s,1H),8.24(dd,J=8.0,1.5Hz,1H),8.18(d,J=9.5Hz,1H),8.07(d,J=1.5Hz,1H),8.02(d,J=8.0Hz,1H),7.81(br.s.,1H),7.78(dd,J=8.0,1.5Hz,1H),7.68(dd,J=7.8,4.8Hz,2H),7.21(d,J=9.5Hz,1H),2.27(s,3H)。
採用流程1(方法A)中所描述之實驗程序藉由使4及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物57。藉由製備型HPLC(條件Q)來純化粗殘餘物,得到6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈57(3.4mg,10.89μmol,產率2.8%)。LC-MS:m/z=313.2[M+H]+;滯留時間1.40分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.92-8.86(m,1H),8.60-8.56(m,1H),8.26-8.20(m,1H),8.18-8.11(m,1H),8.08-8.02(m,1H),7.88-7.79(m,1H),7.72-7.64(m,1H),7.38-7.31(m,1H),7.23-7.15(m,1H),1.87(s,3H).
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自57合成化合物58。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺58(5.1mg,0.015mmol,產率12.1%)。LC-MS:m/z=331.1[M+H]+;滯留時間1.01分鐘;條件C,1H NMR(400MHz,DMSO-d6)δ ppm 9.15-9.10(m,1H),8.54-8.45(m,3H),8.22-8.17(m,1H),8.07(s,1H),8.04-7.99(m,1H),7.97-7.92(m,1H),7.89-7.85(m,1H),7.56(d,J=9.5Hz,1H),7.46-7.40(m,1H),2.15(s,3H)。
採用流程4(方法D)中所描述之實驗程序藉由使4及2-溴-4-氟吡啶反應來合成化合物59。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物59(4.3mg,0.013mmol,產率3.1%),LC-MS:m/z=317[M+H]+;滯留時間1.41分鐘;條件C,1H NMR(400MHz,DMSO-d6)δ ppm 8.93-8.89(m,1H),8.60-8.57(m,1H),8.27-8.19(m,3H),8.03-7.97(m,1H),7.77-7.72(m,1H),7.42-7.37(m,1H),7.34-7.27(m,1H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自59合成化合物60。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物60(7.9mg,0.023mmol,產率18.3%)。LC-MS:m/z=335.1[M+H]+;滯留時間1.03分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.93-8.87(m,1H),8.32-8.20(m,4H),7.98-7.92(m,1H),7.85-7.80(m,1H),7.78-7.72(m,1H),7.68-7.61(m,1H),7.34(d,J=9.3Hz,2H)。
採用流程3(方法C)中所描述之實驗程序藉由使4及6-溴-3-氟-2-甲基吡啶反應來合成化合物61。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物61(140mg,0.424mmol,產率54.2%)。LCMS:m/z=331.1[M+H]+;滯留時間1.59分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.88(dd,J=4.8,1.6Hz,1H),8.60(s,1H),8.25(d,J=9.5Hz,1H),8.17-8.09(m,2H),7.77(t,J=9.0Hz,1H),7.68(dd,J=7.8,4.9Hz,1H),7.38(d,J=9.5Hz,1H),1.86(d,J=2.7Hz,3H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自61合成化合物43。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺43(20mg,0.057mmol,產率19.0%)。LCMS:m/z=349.1;滯留時間1.13分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.86(dd,J=4.8,1.6Hz,1H),8.28(s,1H),8.26-8.20(m,2H),8.03(dd,J=8.7,3.8Hz,1H),7.82-7.58(m,4H),7.32(d,J=9.3Hz,1H),1.88(d,J=2.7Hz,3H)。
採用流程2(方法B)中所描述之實驗程序自4及2-溴-6-異丙基吡啶合成化合物63。藉由製備型HPLC(條件F)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-異丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈63(125mg,3.67mmol,產率37.5%)。LCMS:m/z=341.1[M+H]+;滯留時間1.64分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.87-8.91(m,1H),8.58(s,1H),8.28(d,J=9.54Hz,1H),8.12-8.17(m,1H),8.01-8.06(m,1H),7.84-7.91(m,1H),7.65-7.73(m,1H),7.39(d,J=9.04Hz,1H),7.16-7.24(m,1H),2.68(td,J=1.95,3.64Hz,1H),0.58(d,J=7.03Hz,6H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自4合成化合物64。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-異丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺64(34.9mg,0.096mmol,32.8%)。LCMS:m/z=359.2[M+H]+;滯留時間1.13分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 1.15(dd,J=1.59,4.77Hz,1H),1.82-1.72(m,3H),2.09-2.04(m,1H),2.20-2.12(m,1H),2.33(dd,J=4.77,7.70Hz,2H),2.65-2.57(m,2H),2.84(dd,J=0.98,7.83Hz,1H),7.48-7.40(m,1H),9.49(d,J=6.85Hz,6H)。
採用流程4(方法D)中所描述之實驗程序藉由使4及6-溴-2-氟吡啶反應來合成化合物65。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈65(1.4mg,4.38μmol,產率0.38%)。LCMS:m/z=317.1[M+H]+;滯留時間1.41分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.91(dd,J=1.71,4.65Hz,1H),8.60(s,1H),8.31(d,J=9.54Hz,1H),8.17-8.22(m,1H),8.15(d,J=8.07Hz,1H),8.08-8.13(m,1H),7.73(dd,J=4.89,7.83Hz,1H),7.47(d,J=9.54Hz,1H),7.11-7.18(m,1H).
採用流程5化合物17中所描述之實驗程序藉由使6A(參考文獻:
WO 2013064984 A1)及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(參考文獻:WO 2015157093 A1/WO 2015044172 A1/WO 2014055955 A1)反應來合成化合物6B。藉由矽膠層析(24g RediSep®管柱,用20%-60%乙酸乙酯/石油醚之梯度溶離)來純化粗產物,得到呈淡黃色固體狀之化合物6B(180mg,0.59mmol,產率16.1%)。LCMS:m/z=301.2[M-H]+;滯留時間2.13分鐘;條件E。
採用流程1(方法A)中所描述之實驗程序藉由使6B及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物6C。藉由矽膠層析(RediSep®管柱,用20%乙酸乙酯/石油醚之梯度溶離)來純化粗殘餘物,得到N-(第三丁基)-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-胺6C(0.07g,0.20mmol,39.3%)。LCMS:m/z=358.2[M+H]+;滯留時間1.73;條件E。
將N-(第三丁基)-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-胺6C(0.05g,0.140mmol)及TFA(2mL,26.0mmol)之混合物在室溫下攪拌隔夜。在減壓下蒸發TFA,且藉由製備型HPLC(條件N)來純化殘餘物。合併含有產物之溶離份,且在減壓下濃縮,得到2,2,2-三
氟-N-(6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-基)乙醯胺66(5.7mg,0.14mmol,產率9.7%)。LCMS:m/z=398.1[M+H]+;滯留時間1.27;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 13.63(br s,1H),8.75-8.81(m,1H),8.39(br s,1H),7.98-8.06(m,2H),7.59-7.75(m,5H),7.14-7.19(m,1H),2.12(s,3H)。
向6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈7A(100mg,0.321mmol)於1,4-二噁烷(5mL)及H2O(2mL)混合物中之溶液中添加LiOH(61.5mg,2.57mmol)。將反應混合物在80℃下加熱4小時。隨後用水(20mL)稀釋反應混合物,用1.5N HCl水溶液酸化至pH-5.0,且穿過Celite®床。將濾液蒸發至乾燥。藉由製備型HPLC(方法N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲酸67(4.4mg,0.013mmol,產率4.1%)。LCMS:m/z=330.1[M+H]+;滯留時間1.02分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.39(dd,J=0.98,1.71Hz,1H),8.75(dd,J=1.59,4.77Hz,1H),8.32(s,1H),7.98(dd,J=1.47,7.83Hz,1H),7.67-7.76(m,1H),7.50-7.64(m,3H),7.05-7.16(m,2H),2.09(s,3H)。
向化合物67(0.1g,0.303mmol)於DMF(2mL)中之攪拌溶液中添加HATU(0.23g,0.605mmol)及DIPEA(0.16mL,0.908mmol),接著添加2,2-二氟乙胺(29.4mg,0.363mmol)。將反應混合物在室溫下攪拌18小時。在減壓下濃縮反應混合物,得到粗殘餘物,其藉由製備型HPLC(條件N)來純化,得到呈淺黃色固體狀之N-(2,2-二氟乙基)-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺68(3.2mg,8.05μmol,產率2.7%)。LCMS:m/z=394.1[M+H]+;滯留時間1.40分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.35(dd,J=1.00,2.01Hz,1H),8.87(t,J=6.02Hz,1H),8.75(dd,J=1.51,4.52Hz,1H),8.40(s,1H),7.95-8.01(m,1H),7.68-7.75(m,1H),7.53-7.65(m,3H),7.08-7.17(m,1H),5.95-6.29(m,1H),3.63-3.76(m,2H),2.09(s,3H)。
採用在流程14中對68所描述之實驗程序藉由使67及2,2,2-三氟乙胺反應來合成化合物69。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之6-(6'-甲基-[2,2'-聯吡啶]-3-基)-N-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-3-甲醯胺69(2.1mg,5.05μmol,產率
1.7%)。LCMS:m/z=412.1[M+H]+;滯留時間1.53分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.32-9.36(m,1H),9.08(t,J=6.53Hz,1H),8.75(dd,J=1.76,4.77Hz,1H),8.45(s,1H),7.97-8.02(m,1H),7.68-7.74(m,1H),7.56-7.64(m,3H),7.09-7.18(m,2H),4.05-4.16(m,2H),2.08(s,3H)。
採用在流程14中對68所描述之實驗程序藉由使67及2-甲氧基乙胺反應來合成化合物70。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之N-(2-甲氧基乙基)-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺70(1.7mg,4.34μmol,產率1.4%)。LCMS:m/z=388.2[M+H]+;滯留時間1.3分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.39(dd,J=1.00,2.01Hz,1H),8.73-8.76(m,1H),8.56(d,J=4.02Hz,1H),8.33(d,J=8.03Hz,1H),7.95-8.01(m,1H),7.68-7.75(m,1H),7.57-7.63(m,2H),7.51-7.56(m,1H),7.14(d,J=7.53Hz,1H),7.04-7.10(m,1H),3.40-3.49(m,4H),3.28(s,3H),2.10(s,3H)。
採用在流程14中對68所描述之實驗程序藉由使67及(2H3)甲胺反應來合成化合物71。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之化合物71(0.4mg,1.120μmol,產率0.4%)。LCMS:m/z=347.1[M+H]+;滯留時間0.90分鐘;條件D。1H NMR(400MHz,DMSO-d6)δ ppm 9.36(s,1H),8.74(dd,J=1.59,4.77Hz,1H),8.41(s,1H),8.25(s,1H),7.97(dd,J=1.59,7.70Hz,1H),7.67-7.75(m,1H),7.56-7.63(m,2H),7.53(d,J=9.05Hz,1H),7.13(d,J=7.83Hz,1H),7.06(dd,J=1.71,9.29Hz,1H),2.08(s,3H)。
採用在流程14中對68所描述之實驗程序藉由使67及甲胺反應來合成化合物72。藉由製備型HPLC(條件N)來純化粗殘餘物,得到呈淺黃色固體狀之化合物72(2.4mg,6.64μmol,產率2.2%)。LCMS:m/z=344.1[M+H]+;滯留時間1.22分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.38(dd,J=1.00,2.01Hz,1H),8.73-8.76(m,1H),8.40-8.46(m,1H),8.26(s,1H),7.98(dd,J=1.76,7.78Hz,1H),7.69-7.75(m,1H),7.57-7.63(m,2H),7.50-7.56(m,1H),7.14(d,J=7.53Hz,1H),7.04-7.10(m,1H),2.79(d,J=4.52Hz,3H),2.09(s,3H)。
向57(0.02g,0.064mmol)於水(5mL)中之溶液中添加KOH(0.018g,0.32mmol)。經5分鐘將反應混合物加熱至95℃,且攪拌18小時。使反應混合物冷卻至室溫,過濾出沈澱之固體,且用1N HCl水溶液將濾液酸化至pH 6。經由燒結漏斗過濾沈澱產物,且在真空下乾燥,得到粗殘餘物,其藉由製備型HPLC(條件N)來純化,得到(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲酸73(8.7mg,0.026mmol,產率41.0%)。LCMS:m/z=332.1[M+H]+;滯留時間0.71分鐘;條件C,1H NMR(400MHz,DMSO-d6)δ ppm 12.94(bs,1H),8.89-8.86(m,1H),8.32(s,1H),8.13(s,2H),8.01-7.95(m,1H),7.87-7.82(m,1H),7.72-7.66(m,1H),7.26-7.19(m,2H),1.97(s,3H).
採用在流程14中對68所描述之實驗程序藉由使73及氧雜環丁-3-胺反應來合成化合物74。藉由製備型HPLC(條件N)來純化粗產物,得到6-(6'-甲基-[2,2'-聯吡啶]-3-基)-N-(氧雜環丁-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺6M(11.3mg,0.029mmol,產率16.15%)。LCMS:m/z=387.2[M+H]+;滯留時間1.07分鐘;條件C,1H NMR(400MHz,DMSO-d6)δ ppm 8.89-8.86(m,1H),8.69-8.66(m,1H),8.28(s,2H),
8.26-8.21(m,1H),7.99-7.95(m,1H),7.86-7.81(m,1H),7.73-7.68(m,1H),7.37-7.31(m,1H),7.21-7.15(m,1H),4.95-4.88(m,1H),4.76(s,2H),4.38(s,2H),1.86(s,3H)。
採用在流程14中對68所描述之實驗程序藉由使73及環丙基胺反應來合成化合物75。藉由HPLC(條件N)來純化粗殘餘物,得到N-環丙基-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺75(7.6mg,0.020mmol,產率16.8%)。LCMS:m/z=371.2[M+H]+;滯留時間1.26分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.90-8.83(m,1H),8.25(d,J=2.4Hz,3H),8.15-8.10(m,1H),7.98-7.93(m,1H),7.87-7.81(m,1H),7.73-7.68(m,1H),7.37-7.31(m,1H),7.19-7.13(m,1H),2.77-2.70(m,1H),1.85(s,3H),0.75-0.69(m,2H),0.39-0.33(m,2H)。
向化合物9A(參考文獻:US 2009/0163489 A1)(0.315g,1.24mmol)及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(參考文獻WO 2015157093 A1/WO 2015044172 A1/WO 2014055955 A1)(0.445,1.86mmol)於1,4-二噁烷(9mL)及水(3mL)中之攪拌溶液中添加Na2CO3(0.394g,3.72mmol)。使反應混合物脫氣3分鐘,且隨後向其中添加Pd(PPh3)4(0.143g,0.124mmol),且將所得混合物在100℃下加熱12小時。隨後經由Celite®墊過濾反應混合物,用乙酸乙酯洗滌濾餅,且在減壓下蒸發經合併之濾液,得到粗化合物。其經由矽膠層析(24g RediSep®管柱,用60%乙酸乙酯/石油醚溶離)來純化,得到呈淡黃色固體狀之N-(6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-2-基)乙醯胺9B(211mg,0.736mmol,產率59.4%)。LCMS:m/z=385.0[M+H]+;滯留時間1.49分鐘;條件C。
採用流程1(方法A)中所描述之實驗程序藉由使9B及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物76。藉由製備型HPLC(條件N)來純化粗化合物,得到N-(6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-基)乙醯胺76(7.6mg,0.022mmol,產率12.4%)。LCMS:m/z=344.1[M+H]+;滯留時間1.17分鐘;條件C。1H NMR(400MHz,
DMSO-d6)δ ppm 10.65(s,1H),8.70-8.71(m,1H),8.50(s,1H),8.02(s,1H),7.93-7.95(m,1H),7.69-7.73(m,1H),7.53-7.58(m,2H),7.21(d,J=9.2Hz,1H),7.15(d,J=7.6Hz,1H),6.77(d,J=1.6Hz,1H)2.15(s,3H),2.07(s,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使9B及6-溴-3-氟-2-甲基吡啶反應來合成化合物77。藉由製備型HPLC(條件G)來純化粗化合物,得到N-(6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-基)乙醯胺77(27.3mg,0.073mmol,產率21.0%)。LCMS:m/z=362.1[M+H]+;滯留時間1.29分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 10.8(s,1H),8.72(dd,J=1.6,4.8Hz,1H),8.57(s,1H),8.05(s,1H),7.96(dd,J=1.2,7.6,1H),7.65-7.72(m,2H),7.58-7.61(m,1H),7.32(d,J=9.2Hz,1H),6.90(d,J=8.8Hz,1H),2.11(s,3H),2.09(s,3H)。
採用在流程12中對50所描述之實驗程序藉由使10A(參考文獻:WO 2015086526 A1、WO 2011050245 A1及WO 2009112651 A1)及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(參考文獻:WO 2015157093 A1、WO 2015044172 A1及WO 2014055955 A1)反應來合成化合物10B。藉由矽膠層析(24g RediSep®管柱,用50%乙酸乙酯/石油醚溶離)來純化粗產物。合併含有產物之溶離份,且在減壓下濃縮,得到6-(2-氯吡啶-3-基)咪唑并[1,2-a]吡啶-2-甲酸乙酯10B(0.5g,1.65mmol,產率55.7%)。LCMS:m/z=302.1[M+H]+;滯留時間2.21分鐘;條件E。
採用流程2(方法B)中所描述之實驗程序藉由使10B及6-溴-3-氟-2-甲基吡啶及雙(三丁基錫)反應來合成化合物10C。藉由矽膠層析(24g RediSep®管柱,用40%乙酸乙酯/石油醚溶離)來純化粗產物。合併含有產物之溶離份,且在減壓下濃縮,得到6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-甲酸乙酯10C(0.05g,0.133mmol,產率25.1%)。LCMS:m/z=377.2[M+H]+;滯留時間1.50分鐘;條件E。
向6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-甲酸乙酯10C(0.05g,0.133mmol)於THF(2mL)中之溶液中添加氨(1mL,2.5M),且將反應物在室溫下攪拌隔夜。在減壓下蒸發溶劑,且藉由製備型HPLC(條件N)純化殘餘物,得到化合物78(1.5mg,4.32μmol,產率3.3%)。LCMS:m/z=348.2[M+H]+;滯留時間1.13分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.74(dd,J=1.31,4.68Hz,1H),8.57(s,1H),8.30(s,1H),7.99(dd,J=1.35,7.76Hz,1H),7.75-7.81(m,1H),7.66-7.72(m,2H),7.59(dd,J=4.71,7.76Hz,1H),7.36-7.46(m,2H),6.92(dd,J=9.45,1.62Hz,1H),2.07(d,J=2.75Hz,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使10B及2-溴-6-(三氟甲基)吡啶及雙(三丁基錫)反應來合成化合物10E。藉由矽膠層析(12g,RediSep®管柱,用40%乙酸乙酯/石油醚溶離)來純化粗殘餘物。合併含有產物之溶離份,且在減壓下蒸發,得到6-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-甲酸乙酯10E(0.2g,產率48.7%)。LCMS:m/z=413.3[M+H]+;滯留時間1.14分鐘;條件B。
採用對78之合成所描述的實驗程序藉由使10E及氨反應來合成化合物79。藉由製備型HPLC(方法N)來純化粗殘餘物,得到化合物79(6.5mg,0.017mmol,6.9%)。LCMS m/z=384.1[M+H]+;滯留時間1.40分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.78-8.83(m,1H),8.57-8.60(m,1H),8.26(s,2H),8.17-8.23(m,1H),8.03-8.07(m,1H),7.79-7.84(m,1H),7.64-7.74(m,2H),7.37-7.43(m,2H),6.88-6.94(m,1H)。
採用流程1(方法A)中所描述之實驗程序藉由使10B及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物10G。藉由矽膠層析(12g RediSep®管柱,用40%乙酸乙酯/石油醚溶離)來純化粗產物。合併含有產物之溶離份,且在減壓下濃縮,得到化合物10G(0.06g,0.17mmol,產率38.9%)。LCMS:m/z=359.2[M+H]+;滯留時間1.39分鐘;條件E。
採用對78之合成所描述的實驗程序藉由使10G及氨反應來合成化合物80。藉由製備型HPLC(方法N)來純化粗殘餘物,得到6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-甲醯胺80(21.5mg,產率11.46%)。LCMS:m/z=330.1[M+H]+;滯留時間1.13分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.73-8.77(m,1H),8.58(s,1H),8.30(s,1H),7.97-8.02(m,1H),7.64-7.79(m,3H),7.57-7.63(m,1H),7.40(d,J=9.35Hz,2H),7.18(s,1H),6.88-6.93(m,1H),2.11(s,3H)。
採用在流程16中對9B所描述之實驗程序藉由使11A'(參考文獻:WO2013171640 A1)及6-溴咪唑并[1,2-a]吡啶-3-甲腈11B反應來合成化合物11C。經由矽膠層析(24g RediSep®管柱,用50%乙酸乙酯/石油醚溶離)來純化粗產物。合併含有產物之溶離份且蒸發,得到呈白色固體狀之化合物11C(0.32g,1.17mmol,產率45.3%)。LCMS:m/z=273.2[M+H]+;滯留時間1.73分鐘;條件E。
在氮氣下向6-(2-氯-5-氟吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈11C(0.05g,0.183mmol)及2-甲基-6-(三丁基錫烷基)吡啶(0.070g,0.183mmol)於1,4-二噁烷(2mL)中之脫氣溶液中添加肆(三苯基膦)鈀(0)(0.127g,0.110mmol)。將反應混合物在微波烘箱中在120℃下攪拌1小時,獲得粗殘餘物,其藉由製備型HPLC(條件N)來純化,得到呈灰白色固體狀之6-(5-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈81(4.5mg,0.014mmol,產率7.5%)。LCMS m/z=330.1[M+H]+;滯留時間1.55分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 8.77-8.80(m,1 H)8.68-8.71(m,1 H)8.48(s,1 H)8.11(dd,J=9.29,2.76Hz,1 H)7.61-7.78(m,3 H)7.15-7.24(m,2 H)2.10(s,3 H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自81合成化合物82。藉由製備型HPLC(條件I)來純化粗殘餘物,得到化合物82(22mg,0.063mmol,產率17.38%)。LCMS m/z=348.1[M+H]+;滯留時間0.84分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 9.39(d,J=0.73Hz,1 H)8.32(s,1 H)8.02(dd,J=9.29,2.93Hz,1 H)7.86-7.96(m,1 H)7.94(br.s.,1 H)7.70(d,J=15.41Hz,1 H)7.28-7.45(m,1 H)7.36(br.s.,1 H)7.07-7.09(m,2 H)2.08(s,3 H)。
採用流程3(方法C)中所描述之實驗程序藉由使11C及2-溴-6-(二氟甲基)吡啶反應來合成化合物9F。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物83(65mg,0.18mmol,產率97%)。LCMS:m/z=366.1[M+H]+;滯留時間1.73分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 8.79(d,J=2.69Hz,1 H)8.65(d,J=0.73Hz,1 H)8.47(s,1H)8.00-8.14(m,3 H)7.55-7.66(m,2 H)7.16(dd,J=9.17,1.83Hz,1 H)6.32-6.62(m,1 H)。
採用流程7(方法B)中所描述之實驗程序自83合成化合物84。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物84(7mg,0.018mmol,產率13.3%)。LCMS:m/z=384.1[M+H]+;滯留時間1.12分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 9.41(s,1H)8.81(d,J=2.69Hz,1 H)8.32(s,1 H)8.03-8.12(m,2 H)7.97(d,J=7.83Hz,2 H)7.52-7.62(m,2 H)7.36(br.s.,1 H)7.15(dd,J=9.17,1.83Hz,1 H)6.35-6.68(m,1 H)。
採用流程3(方法C)中所描述之實驗程序藉由使11C及6-溴-3-氟-2-甲基吡啶反應,且隨後類似於19採用流程7(方法B)中所描述之實驗程序使所得氰基化合物水解,來合成化合物85。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物85(12mg,0.033mmol,產率19.1%)。LCMS:m/z=366.1[M+H]+;滯留時間1.32分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 9.39(d,J=0.73Hz,1 H))8.77(d,J=2.4Hz,1 H)8.32(s,1 H)8.02(dd,J=9.29,2.93Hz,1 H)7.86-7.96
(br.s.,1 H)7.70(m,1 H)7.36(br.s.,1 H)7.07-7.09(m,1 H)2.08(s,3 H)
採用如流程16中所示對9B所描述之實驗程序藉由使11B及(2-氯-6-甲基吡啶-3-基)酸反應來合成中間物12A'。藉由矽膠層析(40g RediSep®管柱,用20%-30%乙酸乙酯/石油醚之梯度溶離)來純化粗產物,得到呈灰白色固體狀之化合物12A'(150mg,0.497mmol,產率31.5%)。LCMS:m/z=269[M+H]+;滯留時間1.7分鐘;條件E。
採用流程1(方法A)中所描述之實驗程序藉由使12A'及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物86。藉由製備型HPLC(條件H)來純化粗殘餘物,得到6-(6,6'-二甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈86(85mg,0.149mmol,產率57.2%)。LCMS:m/z=326.1[M+H]+;滯留時間1.45分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.49(dd,J=1.7,1.0Hz,1H),8.44(s,1H),7.95(d,J=7.8Hz,1H),7.74-7.65(m,2H),7.62(s,1H),7.47(d,J=8.1Hz,1H),7.23-7.14(m,2H),2.61(s,3H),2.13(s,3H)。
類似於19採用流程7(方法B)中所描述之實驗程序自86合成化合物87。藉由製備型HPLC(條件O)來純化粗殘餘物,得到6-(6,6'-二甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈87(16.9mg,0.049mmol,產率24.6%)。LCMS:m/z=344.2[M+H]+;滯留時間1.17分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.36(d,J=1.0Hz,1H),8.31(s,1H),7.91-7.81(m,1H),7.71-7.64(m,1H),7.56-7.49(m,2H),7.46(s,1H),7.34(br.s.,1H),7.15-7.03(m,2H),2.60(s,3H),2.12(s,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使12A'及2-溴-6-(二氟甲基)吡啶反應,且隨後類似於19採用流程7(方法B)中所描述之實驗程序使所得氰基化合物水解,來合成化合物88。藉由製備型HPLC(條件H)來純化粗殘餘物,得到化合物88(14.1mg,0.036mmol,產率19.8%)。LCMS:m/z=380.2[M+H]+;滯留時間1.33分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.36(s,1H),8.30(s,1H),8.06(s,1H),7.97-7.85(m,3H),7.61-7.45(m,3H),7.38-7.25(m,1H),7.08(dd,J=9.3,1.7Hz,1H),6.69-6.32(m,1H),2.62(s,3H)。
在50mL燒瓶中,在氮氣下使3-溴-2-氯-6-(三氟甲基)吡啶13A(參考文獻:WO 2015052264 A1)(0.3g,1.15mmol)、雙(頻哪醇根基)二硼烷(0.44g,173mmol)及乙酸鉀(0.19g,2.3mmol)於1,4-二噁烷(3mL)中之溶液脫氣10分鐘,隨後在氮氣下添加PdCl2(dppf)-CH2Cl2加合物(0.094g,0.115mmol)。將反應混合物在80℃下攪拌16小時。其用水(8mL)淬滅,且分離有機層。用乙醚(3×20mL)反萃取水層。用水(2×20mL)、鹽水洗滌經合併之有機層,經無水Na2SO4乾燥,過濾,且在減壓下濃縮濾液,得到呈棕色固體狀之化合物13B(0.25g,0.813mmol,產率70.6%),其未經純化即進行下一步驟。1H NMR(400MHz,CDCl3)δ ppm 7.76-7.90(m,1H)7.47-7.56(m,1H)1.27(s,12H)。
採用在流程16中對67所描述之實驗程序藉由使13B及6-溴咪唑并
[1,2-a]吡啶-3-甲腈11B反應來合成化合物13C。藉由矽膠層析(24g RediSep®管柱,用50%乙酸乙酯/石油醚溶離)來純化粗殘餘物,得到呈白色固體狀之6-(2-氯-6-(三氟甲基)吡啶-3-基)咪唑并[1,2-a]吡啶-3-甲腈13C(0.2g,062mmol,產率57.2%)。LCMS:m/z=323.0[M+H]+;滯留時間2.43分鐘;條件E。
採用在流程18中對81所描述之實驗程序藉由使13C及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物89。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物89(0.15g,0.395mmol,63.8%)。LCMS m/z=380.1[M+H]+;滯留時間1.95分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ 8.72(s,1 H)8.48(s,1 H)8.37(d,J=8.07Hz,1 H)8.13(d,J=8.07Hz,1 H)7.66-7.82(m,3 H)7.20-7.31(m,2 H)2.14(s,3 H)。
類似於19採用流程7(方法B)中所描述之實驗程序自89合成化合物90。藉由製備型HPLC(條件K)來純化粗殘餘物,得到化合物90(11mg,0.027mmol,產率8.66%)。LCMS m/z=398.1[M+H]+;滯留時間1.19分鐘;條件C。1H NMR(400MHz,DMSO-d 6)9.45(s,1 H)
8.30-8.35(m,2H)8.10(d,J=8.07Hz,1 H)7.95(br.s.,1 H)7.72-7.79(m,1 H)7.60(dd,J=8.56,6.11Hz,2 H)7.39(br.s.,1 H)7.10-7.23(m,2 H)2.14(s,3 H)。
在0℃下在氮氣下向3-溴-2-氯異菸鹼酸14A(1g,4.23mmol)於MeOH(20mL)中之攪拌溶液中逐滴添加SOCl2(2.0mL,27.4mmol),且使反應混合物在80℃下攪拌5小時。在減壓下蒸發反應混合物,用飽和碳酸氫鈉水溶液鹼化,其用乙酸乙酯(2×200mL)萃取,用鹽水(20mL)洗滌有機層,經硫酸鈉乾燥,且在減壓下濃縮,得到呈淺棕色油狀之化合物14B(0.8g,3.19mmol,產率76%)。LCMS:m/z=252.2[M+H]+;滯留時間0.9分鐘;條件B。
採用流程5(方法E)中所描述之實驗程序藉由使14B及6-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)咪唑并[1,2-a]吡啶-3-甲腈14C反應來合成化合物14D。藉由矽膠層析(24g RediSep®管柱,用2%-4%甲醇/氯仿之梯度溶離)來純化粗化合物,得到呈淺黃色固體狀之化合物14D(0.25g,0.799mmol,產率40.0%)。LCMS m/z 313.3[M+H]+;滯留時間0.75分鐘;條件B。
採用流程1(方法A)中所描述之實驗程序藉由使14D及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物91。藉由製備型HPLC(方法:N)來純化粗殘餘物,得到化合物91(215mg,產率77%)。LCMS:m/z=370.1[M+H]+;滯留時間1.22分鐘;條件C。1H NMR(400MHz,DMSO-d6):δ ppm 8.93-8.91(m,1H),8.40(s,1H),7.92-7.91(m,1H),7.73-7.67(m,2H),7.61-7.59(m,1H),7.43-7.40(m,1H),7.08-7.07(m,1H),7.40(d,J=8.00Hz,1H),3.65(s,3H),2.00(s,3H)。
在0℃下向3-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6'-甲基-[2,2'-聯吡啶]-4-甲酸甲酯91(0.05g,0.135mmol)於甲醇(0.5mL)四氫呋喃(0.5mL)之混合物中之攪拌溶液中添加NaBH4(5.12mg,0.135mmol),攪拌10分鐘,且使反應混合物在室溫下攪拌1小時。用水(5mL)稀釋反應混合物,且用乙酸乙酯(2×25mL)萃取。用鹽水(1×10mL)洗滌有機層,經無水Na2SO4乾燥,過濾且在減壓下濃縮。藉由製備型HPLC(條件N)來純化殘餘物,得到6-(4-(羥甲基)-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈92(6mg,產率12%);LCMS:m/z=342.1[M+H]+;滯留時間1.11分鐘;條件C。1H NMR(400MHz,DMSO-d6):δ ppm 8.74(d,J=4.00Hz,1H),8.43(s,2H),7.76-7.60(m,4H),7.37-7.40(m,1H),7.02-7.04(m,1H),5.4(bs,1H)4.37-4.40(m,2H),1.99(s,3H)。
在0℃下在氮氣下向6-(4-(羥甲基)-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈92(0.05g,0.527mmol)於CH2Cl2(1mL)中之攪拌溶液中添加戴斯-馬丁高碘烷(Dess-Martin periodinane)(0.093g,0.22mmol),且使反應混合物在室溫下攪拌1小時。反應混合物用飽和碳酸氫鈉水溶液淬滅,用DCM(2×250mL)萃取,經硫酸鈉乾燥,且濃縮,得到6-(4-甲醯基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈14G(0.053g,0.016mmol,產率11.5%),其未經進一步純化即用於下一步驟中。LCMS:m/z=340.1[M+H]+;滯留時間0.54分鐘;條件B。
在-78℃下在氮氣下向6-(4-甲醯基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈14G(0.2g,0.589mmol)於CH2Cl2(2mL)中之攪拌溶液中逐滴添加DAST(0.156mL,1.179mmol)。使反應混合物在室溫下攪拌4小時。使反應混合物冷卻至0℃,用飽和碳酸氫鈉水溶液淬滅,且用乙酸乙酯(2×200mL)萃取。用鹽水(25mL)洗滌有機層,經硫酸鈉乾燥,且濃縮,得到粗產物,其藉由製備型HPLC使用(條件N)來純化,得到6-(4-(二氟甲基)-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈93(115mg,0.30mmol,產率53%);LCMS:m/z=362.1[M+H]+;滯留時間1.54分鐘;條件C;1H NMR(400MHz,DMSO-d6):δ 8.96(d,J=4.00Hz,1H),8.57(s,1H),8.46(s,1H),7.83(d,J=4.00Hz,1H),7.67-7.70(m,3H),7.35-7.37(m,1H),6.88-7.14(m,2H),2.00(s,3H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自93合成化合物94。藉由製備型HPLC(條件N)來純化粗產物,得到6-(4-(二氟甲基)-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺94
(9.1mg,0.024mmol,產率8.7%)。LCMS:m/z=380.1[M+H]+;滯留時間1.09分鐘;條件C。1H NMR(400MHz,DMSO-d6):δ 9.26(s,1H)8.94(d,J=8.00Hz,1H),8.31(s,1H),8.01-7.82(m,2H),7.57-7.68(m,3H),7.25-7.40(m,2H),6.77-7.01(m,2H),2.01(s,3H)。
在室溫下向6-氯吡啶-2-胺13A(參考文獻:WO2014055955A1)(1.0g,7.78mmol)於DMF(10mL)中之溶液中逐份添加NBS(1.384g,7.78mmol),且繼續攪拌2小時。隨後在減壓下蒸發反應混合物,得到粗殘餘物。向此中添加氨水(60mL,25%溶液),且用乙酸乙酯(3×100mL)萃取混合物。經合併之有機層經無水硫酸鈉乾燥,過濾,且在減壓下蒸發濾液,得到粗殘餘物,其藉由矽膠層析(24g RediSep®管柱,用27%-29%乙酸乙酯/石油醚之梯度溶離)來純化,得到呈棕色固體狀之5-溴-6-氯吡啶-2-胺15B(0.4g,1.928mmol,產率24.79%)。LCMS:m/z=207.0[M+H]+;滯留時間1.74分鐘;條件E。
1H NMR(400MHz,DMSO-d6)δ ppm 7.63(d,J=8.5Hz,1H),6.59(s,2H),6.36(d,J=9.0Hz,1H)。
將5-溴-6-氯吡啶-2-胺15B(0.37g,1.784mmol)於Ac2O(5mL,53.0mmol)中之溶液在室溫下攪拌1小時。隨後將反應物傾倒入冰冷水中,攪拌20分鐘,且過濾所獲得之沈澱,得到N-(5-溴-6-氯吡啶-2-基)乙醯胺15C(0.33g,1.323mmol,產率74.2%)。LCMS:m/z=249.0[M+H]+;滯留時間1.86分鐘;條件E。1H NMR(400MHz,DMSO-d6)δ ppm 10.94(s,1H),8.16(d,J=8.5Hz,1H),8.01(d,J=8.5Hz,1H),2.09(s,3H)。
類似於如流程20中所示之13B自N-(5-溴-6-氯吡啶-2-基)乙醯胺15C合成化合物15D。粗產物N-(6-氯-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)乙醯胺15D(0.29g,產率46.2%)未經進一步純化即用於下一步驟。LCMS:m/z=295.2[M-H]+;滯留時間1.27分鐘;條件C。
採用如流程16中所示對化合物9B所描述之實驗程序藉由使N-(6-氯-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)乙醯胺15D及6-溴咪唑并[1,2-a]吡啶-3-甲腈11B反應來合成化合物15E。粗產物15E(0.18g,產率16%)未經進一步純化即用於下一反應。LCMS:m/z=310.2[M-H]+;滯留時間0.65分鐘;條件C。
採用流程1(方法A)中所描述之實驗程序藉由使N-(6-氯-5-(3-氰基咪唑并[1,2-a]吡啶-6-基)吡啶-2-基)乙醯胺15E及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物15F。粗產物N-(3-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6'-甲基-[2,2'-聯吡啶]-6-基)乙醯胺15F(0.04g,產率18.8%)未經進一步純化即用於下一反應。LCMS:m/z=369.5[M-H]+;滯留時間0.54分鐘;條件D。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自15F合成化合物95。藉由製備型HPLC(方法N)來純化粗產物,得到6-(6-
乙醯胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺95(6.6mg,0.017mmol,產率15.7%)。LC-MS:m/z=387.2[M+H]+;滯留時間1.08分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 10.79-10.73(m,1H),9.38-9.32(m,1H),8.31(s,1H),8.26-8.21(m,1H),7.97(s,1H),7.67(s,1H),7.57-7.50(m,1H),7.48-7.28(m,2H),7.19-7.05(m,2H),2.19(s,3H),2.14(s,3H)。
採用在流程22中用於化合物15C之實驗程序自5-溴-6-氯吡啶-3-胺16A合成化合物16B,得到呈棕色固體狀之N-(5-溴-6-氯吡啶-3-基)乙醯胺16B(0.25g,1.002mmol,產率49.5%)。LCMS:m/z=249.0[M+H]+;滯留時間1.53分鐘;條件E。
採用流程5(方法E)中所描述之實驗程序藉由使N-(5-溴-6-氯吡啶-3-基)乙醯胺16B及6-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)咪唑并[1,2-a]吡啶-3-甲腈反應來合成化合物16C。藉由矽膠層析(24g RediSep®管柱,用42%-48%乙酸乙酯/石油醚之梯度溶離來純化粗化合物,得到呈棕色固體狀之N-(6-氯-5-(3-氰基咪唑并[1,2-a]吡啶-6-基)吡啶-3-基)乙醯胺16C(0.3g,0.962mmol,產率48.0%)。LCMS:m/z=312.2[M+H]+;滯留時間1.23分鐘;條件E。
採用流程1(方法A)中所描述之實驗程序藉由使16C及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物96。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物96(12.5mg,0.033mmol,產率17.3%)。LCMS:m/z=369.2[M+H]+;滯留時間1.12分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 10.45(s,1H),8.90(d,J=2.2Hz,1H),8.61-8.49(m,1H),8.47-8.39(m,1H),8.23(d,J=2.4Hz,1H),7.76-7.61(m,3H),7.26(dd,J=9.3,1.7Hz,1H),7.12(d,J=7.3Hz,1H),2.14(s,3H),2.06(s,3H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自96合成化合物97。藉由製備型HPLC(條件N)來純化粗殘餘物,得到化合物97(15.6mg,0.040mmol,產率13.5%)。LCMS:m/z=387.1[M+H]+;滯留時間0.94分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 10.45(s,1H),9.40(s,1H),8.88(d,J=2.2Hz,1H),8.30(s,1H),8.18(d,J=2.4Hz,1H),7.95(br.s.,1H),7.73-7.64(m,1H),7.63-7.57(m,1H),7.54(d,J=9.3Hz,1H),7.36(br.s.,1H),7.12-7.01(m,2H),2.12(s,3H),2.06-2.01(s,3H)。
向N-(3-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6'-甲基-[2,2'-聯吡啶]-5-基)乙醯胺97(0.055g,0.149mmol)於MeOH(4mL)中之溶液中添加LiOH(1mL,2.0mmol)。將反應混合物在80℃下加熱18小時。其隨後經由Celite®床過濾,且在高真空下濃縮濾液,得到棕色油,其藉由製備型HPLC(條件N)來純化,得到化合物98及99。
6-(5-胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺98:(4.6mg,0.013mmol,產率8.95%)。LCMS:m/z=345.1[M+H]+;滯留時間0.44分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.37(s,1H),8.54(s,1H),8.32(s,1H),8.09(s,1H),7.91(br.s.,1H),7.67-7.47(m,3H),7.36(s,1H),7.08-6.93(m,2H),5.76(s,2H),1.98(s,3H)。
6-(5-胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲酸99:(3.3mg,9.56μmol,產率6.40%)。LCMS:m/z 346.1[M+H]+;滯留時間0.5分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.72(br.s,1H),8.41-8.28(m,1H),8.14(br.s.,1H),7.91-7.82(m,1H),7.79-7.71(m,1H),7.65(d,J=9.0Hz,1H),7.32-7.21(m,2H),7.17(br.s.,1H),6.01-5.84(s,2H),2.33(s,3H).
在0℃下在氮氣下向2-氯吡啶-4-胺17A(2g,15.56mmol)於乙酸(20mL)中之攪拌溶液中逐份添加NBS(2.77g,15.56mmol)。隨後使反應混合物在室溫下攪拌1小時。在減壓下移除溶劑,接著與乙醇一起共沸蒸餾。藉由矽膠層析(40g RediSep®管柱,用10%-20%乙酸乙酯/石油醚之梯度溶離)來純化粗化合物,得到呈白色固體狀之化合物15B(2g,9.64mmol,產率62.0%)。LCMS:m/z=209.0[M+H]+;滯留時間0.84分鐘;條件B。
在0℃下向3-溴-2-氯吡啶-4-胺17B(1g,4.82mmol)於DCM(20mL)中之攪拌溶液中添加DIPEA(1.684mL,9.64mmol),接著在氮氣下添加乙醯氯(0.514mL,7.23mmol)。隨後使反應混合物在室溫下攪拌1小時。在減壓下蒸發溶劑,用乙酸乙酯(300mL)稀釋。用飽和碳酸氫鈉(50mL)及鹽水(50mL)洗滌乙酸乙酯層。經無水Na2SO4乾燥有機層,過濾且在減壓下濃縮,得到粗物質N-(3-溴-2-氯吡啶-4-基)乙醯胺17C(0.8g,產率66%)。LCMS:m/z=251.3[M+H]+;滯留時間0.92分鐘;條件B,其未經進一步純化即使用。
類似於17採用流程5(方法E)中所描述之實驗程序自17C合成化合
物17D。藉由矽膠層析(12g REDISEP®管柱,用含4%甲醇/氯仿溶離)來純化粗產物。收集含有產物之溶離份,且在減壓下蒸發,得到呈白色固體狀之化合物17D(0.13g,0.417mmol,產率20.8%)。LCMS:m/z=312.4[M+H]+;滯留時間0.85分鐘;條件B。
採用流程1(方法A)中所描述之實驗程序藉由使17D及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物100。藉由製備型HPLC(條件N)來純化粗殘餘物,得到N-(3-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6'-甲基-[2,2'-聯吡啶]-4-基)乙醯胺100(110mg,產率65%)。LCMS:m/z=369.2[M+H]+;滯留時間1.19分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.02(s,1H),8.62(d,J=4.00Hz,1H),8.46(s,2H),8.16(d,J=4.00Hz,1H),7.74(d,J=8.00Hz,1H),7.64(t,J=16.00Hz,1H),7.53(d,J=8.00Hz,1H),7.27-7.25(m,1H),7.04(d,J=8.00Hz,1H),2.03(s,3H),1.97(s,3H)。
以類似於3A之方式採用流程6(方法A)中所描述之實驗程序自100合成化合物101。藉由製備型HPLC(條件N)來純化粗殘餘物,得到6-(4-胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺101
(10mg,產率34%)。LCMS:m/z=345.1[M+H]+;滯留時間0.66分鐘;條件C。1H NMR(400MHz,DMSO-d6):δ ppm 9.17(s,1H),8.26(s,1H),8.10-8.13(m,1H),7.8(bs,1H),7.53-7.58(m,2H),7.41-7.43(m,1H),7.25(bs,1H)7.12-7.14(m,1H),6.94(d,J=8.00Hz,1H),6.73(d,J=4.00Hz,1H),5.8(s,2H)2.01(s,3H)。
以類似於19之方式採用流程7(方法B)中所描述之實驗程序自100合成化合物102。藉由製備型HPLC(條件N)來純化粗殘餘物,得到102(14mg,產率32%)。LCMS:m/z=387.1[M+H]+;滯留時間0.86分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.21-9.20(m,1H),9.10(s,1H),8.60(d,J=4.00Hz,1H),8.29(s,1H),8.11(d,J=8.00Hz,1H)8.1(bs,1H),7.61-7.57(m,2H),7.40(d,J=8.00Hz,1H),7.14(dd,J=12.00,Hz,1H),7.00(d,J=8.00Hz,1H),6.9(m,1H)2.05(s,3H),1.96(s,3H)。
採用流程5(方法E)中所描述之實驗程序藉由使18A(參考文獻:Journal of Medicinal Chemistry,2014,57,3484-3493)及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(參考文獻:WO 2015157093 A1、WO 2015044172 A1及WO 2014055955 A1)反應來合成化合物18B。藉由矽膠層析(24g RediSep®管柱,用3%-10%甲醇/氯仿之梯度溶離)來純化粗殘餘物。合併含有產物之溶離份,且在減壓下濃縮,得到呈黃色固體狀之化合物18B(320mg,1.242mmol,產率37.4%)。LCMS:m/z=258.0[M+H]+;滯留時間1.08分鐘;條件E。
採用如流程3(方法C)中所示對化合物15所描述之實驗程序藉由使18B及6-溴-3-氟-2-甲基吡啶反應來合成化合物103。藉由製備型HPLC(條件K)來純化粗殘餘物,得到103(13.9mg,0.041mmol,產率14.23%)。LCMS:m/z=333.2[M+H]+;滯留時間1.24分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 8.77(dd,J=4.77,1.59Hz,1 H)8.40(s,1 H)8.25(dd,J=7.70,1.59Hz,1 H)7.76-7.87(m,4 H)7.63(dd,J=7.83,4.65Hz,1 H)7.52(br.s.,1 H)7.40(d,J=8.80Hz,1 H)1.94(s,3 H)。
採用如流程3(方法C)中所示對化合物15所描述之實驗程序藉由使18B及6-溴-3-氟吡啶反應來合成化合物104。藉由製備型HPLC(方法Q)來純化粗殘餘物,得到化合物104(35.6mg,0.111mmol,產率36%)。LCMS:m/z=319.2[M+H]+;滯留時間1.09分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 8.78(dd,J=4.65,1.47Hz,1 H)8.40(s,1 H)8.27-8.32(m,1 H)8.21(d,J=2.69Hz,1 H)8.09(dd,J=8.80,4.65Hz,1 H)7.84-7.91(m,3 H)7.65(dd,J=7.83,4.89Hz,1 H)7.49(br.s.,1 H)7.44(d,J=8.56Hz,1 H)。
採用如流程3(方法C)中所示對化合物15所描述之實驗程序藉由使18B及2-溴-6-(二氟甲基)吡啶反應來合成化合物105。藉由製備型HPLC(方法K)來純化粗殘餘物,得到化合物105(30.1mg,0.085mmol,產率28%)。LCMS:m/z=351.1[M+H]+;滯留時間1.32分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 8.82(dd,J=4.77,1.59Hz,1 H)8.38(s,1 H)8.30(dd,J=7.83,1.71Hz,1 H)8.09-8.18(m,2 H)7.89(d,J=8.56Hz,1 H)7.80(br.s.,1 H)7.69(dd,J=7.83,4.89Hz,1 H)7.60(d,J=6.85Hz,1 H)7.53(d,J=8.80Hz,1 H)7.32(br.s.,1 H)6.19-6.48(t,J=54.8Hz,1 H)。
採用如流程3(方法C)中所示對化合物15所描述之實驗程序藉由使18B及2-溴-6-環丙基吡啶反應來合成化合物106。藉由製備型HPLC(方法:K)來純化粗殘餘物,得到化合物106(48mg,0.141mmol,產率45%)。LCMS:m/z=341.1[M+H]+;滯留時間1.42分鐘;條件C。1H NMR(400MHz,DMSO-d 6)δ ppm 8.76(dd,J=4.77,1.59Hz,1 H)8.41(s,1 H)8.17(dd,J=7.83,1.71Hz,1 H)7.87(d,J=8.80Hz,1 H)7.75-7.85(m,3 H)7.61(dd,J=7.83,4.65Hz,1 H)7.55(br.s.,1 H)7.34(d,J=8.80Hz,1 H)7.25(dd,J=7.34,1.22Hz,1 H)1.73-1.77(m,1 H)0.402-0.358(m,2 H)0.137-0.164(m,2 H)。
採用如流程16中所示對化合物9B所描述之實驗程序藉由使19A(參考文獻:Angew.Chem.Int.Ed. 2014,53,305-309)及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶反應來合成化合物19B。藉由矽膠層析(40g RediSep®管柱,用35%乙酸乙酯/石油醚之梯度溶離)來純化粗殘餘物,得到6-(2-氯吡啶-3-基)喹唑啉-4-胺19B(0.6g,
2.337mmol,產率52.4%)。LCMS:m/z=257.2[M+H]+;滯留時間1.06分鐘;條件E。
採用流程2(方法B)中所描述之實驗程序藉由使19B及6-溴-2-乙基吡啶反應來合成化合物107。藉由製備型HPLC(方法:F)來純化粗殘餘物,得到化合物107(4.2mg,0.012mmol,產率2.09%)。LCMS:m/z=328.2[M+H]+;滯留時間1.21分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.83(s,1H),8.80-8.76(m,1H),8.41(s,1H),7.97(dd,J=7.9,1.6Hz,1H),7.83-7.78(m,2H),7.67-7.61(m,3H),7.26-6.93(m,3H),2.30(d,J=7.6Hz,2H),0.60-0.50(m,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使19B及2-溴-6-異丙基吡啶反應來合成化合物108。藉由製備型HPLC(方法N)來純化粗殘餘物,得到化合物108(14.6mg,0.04mmol,產率7.03%)。LCMS:m/z=342.2[M+H]+;滯留時間1.36分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.75-8.67(m,1H),8.33(s,1H),8.17(d,J=1.5Hz,1H),8.00-7.90(m,1H),7.83-7.71(m,2H),7.69-7.52(m,3H),7.43(d,J=8.6Hz,1H),7.25(dd,J=8.6,1.7Hz,1H),7.10(d,J=7.3Hz,1H),2.65-2.54(m,1H),0.62(d,J=6.8Hz,6H)。
採用流程2(方法B)中所描述之實驗程序藉由使19B及2-溴-6-(二氟甲基)吡啶反應來合成化合物109。藉由製備型HPLC(方法K)來純化粗殘餘物,得到化合物109(0.015g,0.042mmol,產率10.7%)。LCMS:m/z=350.2[M+H]+;滯留時間1.08分鐘;條件E。1H NMR(400MHz,DMSO-d6)δ ppm 8.77(dd,J=5.0,1.5Hz,1H),8.36(s,1H),8.21(d,J=1.5Hz,1H),8.08-8.00(m,2H),7.93(d,J=8.0Hz,1H),7.67(dd,J=8.0,4.5Hz,3H),7.59(d,J=8.0Hz,1H),7.44(d,J=9.0Hz,1H),7.29(dd,J=8.8,1.8Hz,1H),1.82(s,1H)。
採用流程2(方法B)中所描述之實驗程序藉由使19B及6-溴-3-氟-2-甲基吡啶反應來合成化合物110。藉由製備型HPLC(方法K)來純化粗殘餘物,得到化合物110(15mg,0.044mmol,產率11.3%)。LCMS:m/z=332.2[M+H]+;滯留時間1.03分鐘;條件E。1H NMR(400MHz,DMSO-d6)δ ppm 8.72(dd,J=4.8,1.8Hz,1H),8.37(s,1H),8.20(d,J=2.0Hz,1H),7.97(dd,J=7.8,1.8Hz,1H),7.74-7.63(m,4H),7.60(dd,J=7.5,4.5Hz,1H),7.47(d,J=8.5Hz,1H),7.30(dd,J=8.5,2.0Hz,1H),2.03(d,J=3.0Hz,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使19B及2-溴-6-環丙基吡啶反應來合成化合物111。藉由製備型HPLC(方法:N)來純化粗殘餘物,得到化合物111(31.2mg,0.091mmol,產率11.7%)。LCMS:m/z=340.1[M+H]+;滯留時間1.38分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.68-8.72(m,1H),8.35-8.38(m,1H),8.15-8.19(m,1H),7.89-7.94(m,1H),7.62-7.77(m,4H),7.55-7.61(m,1H),7.43-7.47(m,1H),7.16-7.23(m,2H),1.70-1.79(m,1H),0.33-0.41(m,2H),-0.13-0.06(m,2H)。
採用流程5(方法E)中所描述之實驗程序藉由使20A及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(參考文獻:WO 2015157093 A1、WO 2015044172 A1及WO 2014055955 A1)反應來合成化合物20B。藉由矽膠層析(40g RediSep®管柱,用50%乙酸乙酯/石油醚溶離)來純化粗產物,得到呈淡黃色固體狀之化合物20B(2.32g,9.61mmol,產率67.0%)。LCMS:m/z=242.0[M+H]+;滯留時間1.66分
鐘;條件C。
採用流程2(方法B)中所描述之實驗程序藉由使20B及2-甲基-3-氟-6-溴吡啶反應來合成化合物112。藉由製備型HPLC(方法:N)來純化粗殘餘物,得到化合物112(79.9mg,0.253mmol,產率40.7%)。LCMS:m/z=317.2[M+H]+;滯留時間1.51分鐘;條件C。1H NMR(400MHz,DMSO-d6):δ ppm 8.94(s,2H),8.76(dd,J=1.2,4.8Hz,1H),8.05-8.07(m,1H),7.92-7.97(m,2H),7.74-7.77(m,1H),7.61-7.69(m,2H),7.51-7.53(m,1H),1.93(d,J=2.8Hz,3H)。
採用流程1(方法A)中所描述之實驗程序藉由使20B及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物113。藉由製備型HPLC(方法:N)來純化粗殘餘物,得到6-(6'-甲基-[2,2'-聯吡啶]-3-基)喹喏啉113(68.6mg,0.230mmol,產率55.6%)。LCMS:m/z=299.1[M+H]+;滯留時間1.41分鐘;條件C。1H NMR(400MHz,DMSO-d6):δ ppm 8.92(s,2H),8.74-8.76(m,1H),8.05-8.07(m,1H),7.90-7.94(m,2H),7.69-7.73(m,1H),7.60-7.63(m,2H),7.51(dd,J=2.0,8.8Hz,1H),7.11(d,J=7.6Hz,1H),1.97(s,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使20B及2-溴-6-(三氟甲基)吡啶反應來合成化合物114。藉由製備型HPLC(方法:H)來純化粗殘餘物,得到6-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)喹喏啉114(56.9mg,0.162mmol,產率39.0%)。LCMS:m/z=353.1[M+H]+;滯留時間1.75分鐘;條件C。1H NMR(400MHz,DMSO-d6):δ ppm 8.93(s,s,2H),8.83-8.84(m,1H),8.26(d,J=8.0Hz,1H),8.12-8.20(m,2H),7.96(d,J=8.4Hz,1H),7.98(d,J=1.6Hz,1H),7.76(d,7.6Hz,1H),7.71(dd,J=4.8,7.6Hz,1H),7.54(dd,J=2.0,8.8Hz,1H)。
在-78℃下向5-溴-1H-吲唑20(5g,25.4mmol)於THF(100mL)中之溶液中添加LiHMDS(30.5mL,30.5mmol),且將反應混合物在相同溫度下攪拌30分鐘。隨後添加2-(三甲基矽烷基)乙氧基甲基氯化物(6.75mL,38.1mmol),且使反應混合物緩慢達到室溫且攪拌16小
時。反應混合物用飽和NH4Cl淬滅。用乙酸乙酯(3×100mL)反萃取水層。用10% NaHCO3(3×150mL)溶液及鹽水洗滌經合併之有機層。有機層經Na2SO4乾燥,過濾且濃縮,得到呈淺黃色液體狀之粗產物。藉由矽膠層析(120g RediSep®管柱,用1%-5%乙酸乙酯/石油醚之梯度溶離)來純化粗殘餘物,得到呈淡黃色液體狀之5-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑21B(8.13g,24.84mmol,產率98%)LCMS:m/z=327.0[M+H]+;滯留時間3.76分鐘;條件E。
採用如流程16中所示對化合物9B所描述之實驗程序藉由使21B及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)反應來合成化合物21C。藉由矽膠層析(40g RediSep®管柱,用5%-10%乙酸乙酯/石油醚之梯度溶離)來純化粗殘餘物,得到呈淡黃色固體狀之5-(2-氯吡啶-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑21C(1.925g,5.35mmol,產率50.0%)。LCMS:m/z=360.3[M+H]+;滯留時間1.21分鐘;條件B。
採用流程2(方法B)中所描述之實驗程序藉由使21C及2-溴-6-(二氟甲基)吡啶(95mg,0.458mmol)反應來合成化合物21D。藉由矽膠
層析(24g RediSep®®管柱,用5%-10%甲醇/氯仿之梯度溶離)來純化粗殘餘物,得到5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑21D(93mg,0.205mmol,產率49.3%)。LCMS:m/z=453.7[M+H]+;滯留時間1.1分鐘;條件B。
用TFA(8mL,104mmol)處理5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑21D(110mg,0.243mmol),且將反應混合物在室溫下攪拌12小時。在減壓下移除揮發物,且將殘餘物溶解於甲醇(10mL)及氫氧化銨(8mL,205mmol)中且攪拌12小時。此後,在減壓下蒸發反應混合物,獲得粗化合物,其藉由製備型HPLC(方法:H)來純化,得到5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1H-吲唑115(37.5mg,0.116mmol,產率47.9%)。LCMS:m/z=323.1[M+H]+;滯留時間1.14分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 13.03(s,1H),8.71(dd,J=1.6,4.8Hz,1H),7.93-8.01(m,3H),7.61-7.68(m,3H),7.57(d,J=7.6Hz,1H),7.36(d,J=8.8Hz,1H),6.96-7.00(m,1H),6.58(t,J=55.2Hz,1H)。
採用流程2(方法B)中所描述之實驗程序藉由使21C及2-溴-5-氟吡
啶反應來合成化合物21F。藉由矽膠層析(24g RediSep®®管柱,用5%-10%甲醇/氯仿之梯度溶離)來純化粗殘餘物,得到5-(5'-氟-[2,2'-聯吡啶]-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑21F(105mg,0.250mmol,產率59.9%)。LCMS:m/z=421.1[M+H]+;滯留時間3.13分鐘;條件E。
採用在流程28中對化合物115所描述之實驗程序藉由使21F反應來合成化合物116。藉由製備型HPLC(方法:H)來純化粗殘餘物,得到5-(5'-氟-[2,2'-聯吡啶]-3-基)-1H-吲唑116(23.2mg,0.080mmol,產率28.0%)。LCMS:m/z=291.1[M+H]+;滯留時間1.32分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.65-8.67(m,1H),8.29(d,J=2.8Hz,1H),8.02(s,1H),7.92-7.95(m,1H),7.68-7.76(m,2H),7.60(s,1H),7.55-7.58(m,1H),7.37(d,J=8.8Hz,1H),6.95-6.98(m,1H)。
採用流程2(方法B)中所描述之實驗程序藉由使21C及6-溴-3-氟-2-甲基吡啶反應來合成化合物21H。藉由矽膠層析(24g RediSep®管柱,用5%-10%甲醇/氯仿之梯度溶離)來純化粗殘餘物,得到呈淡黃色固體狀之5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)-1-((2-(三甲基矽烷基)乙
氧基)甲基)-1H-吲唑21H(135mg,0.311mmol,產率74.5%)。LCMS:m/z=435.4[M+H]+;滯留時間3.3分鐘;條件E。
採用如流程28中所示對化合物115所描述之實驗程序藉由使21H反應來合成化合物117。藉由製備型HPLC(方法:H)來純化粗殘餘物,得到5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)-1H-吲唑117(13mg,0.043mmol,產率14.28%)。LCMS:m/z=305.1[M+H]+;滯留時間1.24分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 13.03(s,1H),8.65(dd,J=1.6,4.8Hz,1H),8.03(s,1H),7.92(dd,J=1.6,8.0Hz,1H),7.53-7.60(m,3H),7.37-7.42(m,2H),6.97-7.00(m,1H),2.13(d,J=2.8Hz,3H)。
採用如流程16中所示對化合物9B所描述之實驗程序藉由使22A(參考文獻:US 20140194441 A1)及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶反應來合成化合物22B。藉由矽膠層析(40g RediSep®管柱,用5%-10%乙酸乙酯/石油醚之梯度溶離)來純化粗殘餘物,得到5-(2-氯吡啶-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑-3-甲醛22B(1.202g,3.10mmol,產率73.4%)。LCMS:m/z=388.2[M+H]+;滯留時間3.52分鐘;條件E。
採用流程2(方法2)中所描述之實驗程序藉由使22B及2-溴-6-(二氟甲基)吡啶反應來合成化合物22C。藉由矽膠層析(24g RediSep®管柱,用5%-10%乙酸乙酯/石油醚之梯度溶離)來純化粗殘餘物,得到5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑-3-甲醛22C(335mg,0.697mmol,產率49.2%)。LCMS:m/z=481.2[M+H]+;滯留時間3.56分鐘;條件E。
在0℃下向5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑-3-甲醛22C(100mg,0.208mmol)於DCM(5mL)中之攪拌溶液中添加DAST(0.055mL,0.416mmol)。使反應混合物升溫至室溫,且攪拌16小時。用DCM(20ml)稀釋反應混合物,且將其傾倒入經冰冷卻之10%NaHCO3水溶液(20mL)中。分離有機層,且用DCM(3×15mL)反萃取水層。經Na2SO4乾燥經合併之有機層,在減壓下濃縮,得到淡黃色半固體塊。藉由矽膠層析(24g RediSep®管柱,用10%-30%乙酸乙酯/石油醚之梯度溶離)來純化粗殘餘物,得到3-(二氟甲基)-5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吲唑22D(72mg,0.143mmol,產率68.8%)。LCMS:m/z=503.2[M+H]+;滯留時間3.47分鐘;條件E。
採用如流程29中所示對化合物115所描述之實驗程序自22D合成化合物118。藉由製備型HPLC(方法:H)來純化粗殘餘物,得到3-(二氟甲基)-5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1H-吲唑115(9.7mg,0.026mmol,產率12.35%)。LCMS:m/z=373.1[M+H]+;滯留時間1.8分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ=13.57(s,1H),
8.72-8.74(m,1H),7.97-8.00(m,2H),7.74-7.76(m,1H),7.56-7.64(m,4H),7.27(t,J=54.0Hz,1H),7.14-7.18(m,1H),6.52(J=54.8Hz,1H)。
採用如流程16中所示對化合物9B所描述之實驗程序藉由使23A[參考文獻:Heterocycles(2010),80(2),1359-1379]及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶反應來合成化合物23B。使用矽膠層析(24g RediSep®管柱,用50%乙酸乙酯/石油醚之梯度溶離)來純化粗物質。合併含有產物之溶離份,且在減壓下蒸發,得到化合物5-(2-氯吡啶-3-基)吡唑并[1,5-a]嘧啶-3-甲腈23B(900mg,3.52mmol,產率62.9%)。LCMS:m/z=256.1[M+H]+;滯留時間0.64分鐘;條件B。
採用在流程18中對化合物81所描述之實驗程序藉由使23B及2-甲
基-6-(三丁基錫烷基)吡啶反應來合成化合物119。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲腈119(120mg,0.384mmol,產率49.1%)。LCMS:m/z=313.1[M+H]+;滯留時間1.44分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ=9.19(d,J=7.3Hz,1H),8.85(dd,J=4.6,1.7Hz,1H),8.81(s,1H),8.14(dd,J=7.8,1.7Hz,1H),8.00(d,J=7.8Hz,1H),7.83(t,J=7.7Hz,1H),7.66(dd,J=7.7,4.8Hz,1H),7.19(d,J=7.6Hz,1H),7.07(d,J=7.1Hz,1H),1.90(s,3H)
類似於3A採用流程6(方法A)中所描述之實驗程序自119合成化合物120。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺120(10.6mg,0.032mmol,產率10%)。LCMS:m/z=332.1[M+H]+;滯留時間1.1分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.16(d,J=7.1Hz,1H),8.83(dd,J=4.8,1.6Hz,1H),8.51(s,1H),8.25(dd,J=7.7,1.6Hz,1H),7.90-7.77(m,2H),7.67(dd,J=7.7,4.8Hz,1H),7.31(br.s.,1H),7.19(d,J=7.3Hz,1H),7.08-6.98(m,2H),1.95(s,3H)。
採用流程2(方法B)中所描述之實驗程序藉由使23B及2-溴-6-(三氟甲基)吡啶反應來合成化合物121。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲腈121(140mg,0.382mmol,產率48.9%)。LCMS:m/z=367.1[M+H]+;滯留時間1.72分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.30(d,J=7.1Hz,1H),8.92(dd,J=4.6,1.5Hz,1H),8.79(s,1H),8.49(d,J=7.8Hz,1H),8.29-8.19(m,2H),7.83(d,J=7.8Hz,1H),7.75(dd,J=7.7,4.8Hz,1H),7.31(d,J=7.1Hz,1H)。
採用流程3(方法C)中所描述之實驗程序藉由使23B及6-溴-3-氟-2-甲基吡啶反應來合成化合物122。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲腈122(130mg,0.394mmol,產率50.3%)。LCMS:m/z=331.2[M+H]+;滯留時間1.55分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.30(d,J=7.1Hz,1H),8.92(dd,J=4.6,1.5Hz,1H),8.79(s,1H),8.49(d,J=7.8Hz,1H),8.29-8.19(m,2H),7.83(d,J=7.8Hz,1H),7.75(dd,J=7.7,4.8Hz,1H),7.31(d,J=7.1Hz,1H)。
採用如流程16中所示對化合物9B所描述之實驗程序藉由使24A(參考文獻:WO 2013059587 A1)及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶反應來合成化合物24B。使用矽膠層析(24g RediSep®管柱,用50%乙酸乙酯/石油醚之梯度溶離)來純化粗物質。合併含有產物之溶離份,且在減壓下蒸發,得到5-(2-氯吡啶-3-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯24B(1g,3.30mmol,產率83%)。LCMS:m/z=303.1[M+H]+;滯留時間0.82分鐘;條件B。
採用流程3(方法C)中所描述之實驗程序藉由使24B及2-溴-6-(三氟甲基)吡啶反應來合成化合物123。藉由製備型HPLC(條件N)來純化
粗化合物,得到5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯123(180mg,0.435mmol,產率65.9%)。LCMS:m/z=414.1[M+H]+;滯留時間1.81分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.18(d,J=7.1Hz,1H),8.90(dd,J=4.8,1.6Hz,1H),8.58(s,1H),8.45(d,J=8.1Hz,1H),8.28-8.17(m,2H),7.82-7.72(m,2H),7.18(d,J=7.1Hz,1H),4.19(q,J=7.1Hz,2H),1.22(t,J=7.1Hz,3H)。
在8mL小瓶中,添加5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯23B(120mg,0.290mmol)於THF(2mL)及水(1mL)中之溶液。使混合物冷卻至0℃,且添加LiOH(6.95mg,0.290mmol)。隨後,將反應混合物在50℃下加熱12小時。使用1N HCl水溶液使反應混合物酸化,且完全蒸發,得到粗產物,其藉由製備型HPLC(條件N)來純化,得到5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸124(22.5mg,0.058mmol,產率20.1%)。LCMS:m/z=386.1[M+H]+;滯留時間0.97分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.06(d,J=7.3Hz,1H),8.89(d,J=3.7Hz,1H),8.46(d,J=7.6Hz,2H),8.27-8.14(m,2H),7.80(d,J=7.6Hz,1H),7.73(dd,J=7.6,4.9Hz,1H),6.99(d,J=6.6Hz,1H)。
採用如流程14中所示對化合物68所描述之實驗程序藉由使124及甲胺反應來合成化合物125。藉由製備型HPLC(條件N)來純化粗化合物,得到N-甲基-5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺125(1.1mg,2.76μmol,產率3.6%)。LCMS:m/z=399.1[M+H]+;滯留時間1.466分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.26(d,J=7.3Hz,1H),8.93-8.88(m,1H),8.49(s,1H),8.42(d,J=8.1Hz,1H),8.37-8.24(m,2H),7.84-7.73(m,2H),7.33-7.27(m,1H),7.14(d,J=4.6Hz,1H),2.71-2.65(m,3H)。
採用如流程14中所示對化合物68所描述之實驗程序藉由使124及環丙胺反應來合成化合物126。藉由製備型HPLC(條件N)來純化粗化合物,得到N-環丙基-5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺126(5.8mg,0.014mmol,產率17.55%。LCMS:m/z=425.1[M+H]+;滯留時間1.617分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.30(d,J=7.1Hz,1H),8.91(dd,J=4.6,1.5Hz,1H),8.50(s,1H),8.43(d,J=7.8Hz,1H),8.34-8.25(m,2H),7.83(d,J=7.8Hz,1H),7.77(dd,J=7.8,.4.9Hz,1H),7.35(d,J=7.3Hz,1H),7.20(d,J=3.2Hz,1H),2.65-2.57(m,1H),0.71-0.63(m,2H),0.29-0.22(m,
2H)。
採用如流程18中所示對化合物81所描述之實驗程序藉由使24B及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物24G。使用矽膠層析(24g RediSep®管柱,用50%乙酸乙酯/石油醚之梯度溶離)來純化粗化合物。合併含有產物之溶離份,且在減壓下蒸發,得到5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯24G(200mg,0.557mmol,產率67.4%)。LCMS:m/z=360.1[M+H]+;滯留時間0.84分鐘;條件B。
採用如流程31中所示對化合物124所描述之實驗程序自24G合成化合物24H。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸24H(120mg,0.362mmol,產率100%)。LCMS:m/z=332.1[M+H]+;滯留時間0.86分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.99(d,J=7.1Hz,1H),8.83(dd,J=4.8,1.6Hz,1H),8.49(s,1H),8.11(dd,J=7.7,1.6Hz,1H),7.97(d,J=7.8Hz,1H),7.81(t,J=7.7Hz,1H),7.65(dd,J=7.8,4.9Hz,1H),7.18(d,J=7.6Hz,1H),6.78(d,J=7.1Hz,1H),1.93(s,3H)。
採用如流程14中所示對化合物68所描述之實驗程序自24H合成化合物127。藉由製備型HPLC(條件N)來純化粗化合物,得到N-甲基-5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺127(1mg,2.90μmol,產率3.2%)。LCMS:m/z=345.2[M+H]+;滯留時間1.08分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.17(d,J=7.3Hz,1H),8.83(dd,J=4.8,1.6Hz,1H),8.50(s,1H),8.27(dd,J=7.8,1.7Hz,1H),7.91-7.80(m,2H),7.67(dd,J=7.8,4.6Hz,1H),7.31(d,J=4.9Hz,1H),7.18(d,J=7.3Hz,1H),7.14-7.09(m,1H),2.74(d,J=4.9Hz,4H),1.94-1.90(m,3H)。
採用流程14(化合物68)中所描述之實驗程序自24H合成化合物128。藉由製備型HPLC(條件N)來純化粗化合物,得到N-環丙基-5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺128(3.4mg,9.18μmol,產率10.1%)。LCMS:m/z=371.1;滯留時間1.13分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.21(d,J=7.1Hz,1H),8.84(dd,J=4.8,1.6Hz,1H),8.51(s,1H),8.24(dd,J=7.7,1.6Hz,1H),7.94-7.80(m,2H),7.68(dd,J=7.7,4.8Hz,1H),7.41(d,J=3.4Hz,
1H),7.21-7.11(m,2H),2.72-2.65(m,1H),1.90(s,2H),1.94-1.86(m,3H),0.73-0.65(m,1H),0.38-0.27(m,1H)。
採用如流程14中所示對化合物68所描述之實驗程序自24H合成化合物129。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-甲基-[2,2'-聯吡啶]-3-基)-N-(氧雜環丁-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺129(16.5mg,0.043mmol,產率47.2%)。LCMS:m/z=387.1[M+H]+;滯留時間0.99分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.22(d,J=7.3Hz,1H),8.85(dd,J=4.8,1.6Hz,1H),8.54(s,1H),8.31(dd,J=7.8,1.7Hz,1H),7.95(dd,J=12.2,7.1Hz,2H),7.87-7.80(m,1H),7.70(dd,J=7.8,4.9Hz,1H),7.22-7.12(m,2H),4.90(dq,J=13.8,6.6Hz,1H),4.75(t,J=7.0Hz,2H),4.36(t,J=6.5Hz,2H),1.91(s,3H)。
採用流程3(方法C)中所描述之實驗程序藉由使24B及6-溴-3-氟-2-甲基吡啶反應來合成化合物130。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶
-3-甲酸乙酯130(180mg,0.477mmol,產率72.2%)。LCMS:m/z=378.1[M+H]+;滯留時間1.66分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ=9.37(d,J=7.1Hz,1H),9.10(dd,J=4.8,1.6Hz,1H),8.87(s,1H),8.40(dd,J=7.8,1.7Hz,1H),8.32(dd,J=8.4,4.0Hz,1H),8.03(t,J=9.0Hz,1H),7.93(dd,J=7.8,4.9Hz,1H),7.25(d,J=7.3Hz,1H),4.51(q,J=7.1Hz,2H),2.16(d,J=2.7Hz,3H),1.53(t,J=7.1Hz,3H)。
採用如流程31中所示對化合物124所描述之實驗程序自130合成化合物131。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸131(15.4mg,0.044mmol,產率13.8%)。LCMS:m/z=350.2[M+H]+;滯留時間0.67分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.87(d,J=7.1Hz,1H),8.80(dd,J=4.6,1.7Hz,1H),8.32(s,1H),8.11(dd,J=7.7,1.6Hz,1H),8.02(dd,J=8.6,3.7Hz,1H),7.74(t,J=9.0Hz,1H),7.63(dd,J=7.7,4.8Hz,1H),6.63(d,J=7.1Hz,1H),1.96(d,J=2.7Hz,3H)。
採用如流程14中所示對化合物68所描述之實驗程序自131合成化
合物132。藉由製備型HPLC(條件N)來純化粗化合物,得到N-環丙基-5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺132(1.8mg,4.63μmol,產率5.40%)。LCMS:m/z=389.1[M+H]+;滯留時間1.475分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.21(d,J=7.3Hz,1H),8.84(dd,J=4.6,1.2Hz,1H),8.53(s,1H),8.26(d,J=7.6Hz,1H),8.00(dd,J=8.7,3.8Hz,1H),7.80(t,J=9.0Hz,1H),7.69(dd,J=7.8,4.6Hz,1H),7.45(d,J=3.7Hz,1H),7.16(d,J=7.1Hz,1H),1.90(d,J=2.7Hz,3H),0.77-0.67(m,2H),0.38-0.30(m,2H)。
採用如流程14中所示對化合物68所描述之實驗程序自131合成化合物133。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)-N-(氧雜環丁-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺133(2.2mg,5.44μmol,產率6.3%)。LCMS:m/z=405.1[M+H]+;滯留時間1.31分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 9.02(d,J=7.3Hz,1H),8.83(dd,J=4.8,1.6Hz,1H),8.53(s,1H),8.13-8.03(m,2H),7.76(t,J=9.2Hz,1H),7.66(dd,J=7.8,4.6Hz,1H),6.86(d,J=7.3Hz,1H),4.80(t,J=5.5Hz,1H),4.38-4.31(m,1H),4.28-4.12(m,2H),3.59(dt,J=10.0,5.0Hz,1H),3.46-3.37(m,1H),1.91(d,J=2.7Hz,3H)。
採用流程3(方法C)中所描述之實驗程序藉由使24B及2-溴-6-(二氟甲基)吡啶反應來合成化合物134。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯134(26mg,0.066mmol,產率19.91%)。LCMS:m/z=396.1[M+H]+;滯留時間1.63分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ=9.10(d,J=7.3Hz,1H),8.88(dd,J=4.8,1.6Hz,1H),8.57(s,1H),8.30(d,J=7.1Hz,1H),8.22-8.10(m,2H),7.72(dd,J=7.8,4.6Hz,1H),7.59(d,J=7.6Hz,1H),7.04(d,J=7.1Hz,1H),6.58-6.24(m,1H),4.21(q,J=7.1Hz,1H),1.24(t,J=7.1Hz,3H)。
採用如流程31中所示對化合物124所描述之實驗程序自134合成化合物135。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸135(6.2mg,0.017mmol,產率35.1%)。LCMS:m/z=368.1[M+H]+;滯留時間0.91分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.92(d,J=7.5Hz,1H),8.88-8.85(m,1H),8.40(s,1H),8.31-8.26(m,1H),8.19-8.11(m,2H),7.70(dd,J=7.8,4.8Hz,1H),7.61(d,J=7.5Hz,
1H),6.75(d,J=7.5Hz,1H),6.59-6.26(m,1H)。
採用如流程16中所示對化合物9B所描述之實驗程序藉由使25A(參考文獻:WO 2014074657 A1)及2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶反應來合成化合物25B。使用矽膠層析(24g RediSep®管柱,用50%乙酸乙酯/石油醚之梯度溶離)來純化粗產物。合併含有產物之溶離份,且在減壓下蒸發,得到5-(2-氯吡啶-3-基)吡唑并[1,5-a]嘧啶25B(1g,4.34mmol,產率66.6%)。LCMS:m/z=231.3[M+H]+;滯留時間0.76分鐘;條件B。
採用流程2(方法B)中所描述之實驗程序藉由使25B及2-溴-6-(三氟甲基)吡啶反應來合成化合物136。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶136(11.8mg,0.035mmol,產率7.97%)。LCMS:m/z=342.1[M+H]+;滯留時間1.61分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.99(d,J=7.3Hz,1H),8.86(dd,J=4.8,1.6Hz,1H),8.41(d,
J=7.8Hz,1H),8.27-8.12(m,3H),7.80(d,J=7.8Hz,1H),7.70(dd,J=7.8,4.9Hz,1H),6.85(d,J=7.3Hz,1H),6.57(d,J=2.2Hz,1H)。
採用流程3(方法C)中所描述之實驗程序藉由使25B及6-溴-3-氟-2-甲基吡啶反應來合成化合物137。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶137(10.2mg,0.033mmol,產率7.7%)。LCMS:m/z=306.1[M+H]+;滯留時間1.423分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ=8.94(d,J=7.1Hz,1H),8.79(dd,J=4.8,1.6Hz,1H),8.20(d,J=2.4Hz,1H),8.11(dd,J=7.7,1.6Hz,1H),8.00(dd,J=8.6,3.9Hz,1H),7.75(t,J=9.2Hz,1H),7.62(dd,J=7.8,4.6Hz,1H),6.72-6.64(m,2H),1.92(d,J=2.7Hz,3H)。
採用如流程18中所示對化合物81所描述之實驗程序藉由使25B及2-甲基-6-(三丁基錫烷基)吡啶反應來合成化合物138。藉由製備型HPLC(條件N)來純化粗化合物,得到5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶138(61mg,0.212mmol,產率98%)。LCMS:m/z=288.1[M+H]+;滯留時間1.28分鐘;條件C。1H NMR(400MHz,DMSO-d6)δ ppm 8.91(dd,J=7.3,0.7Hz,1H),8.80(dd,J=4.6,1.7Hz,1H),8.19(d,./=2.4Hz,1H),8.10(dd,J=7.6,1.7Hz,1H),7.90(d,J=7.6
Hz,1H),7.84-7.76(m,1H),7.61(dd,J=7.8,4.9Hz,1H),7.17(d,J=7.3Hz,1H),6.68-6.60(m,2H),1.94(s,3H)。
對下文所報導之化合物的分析在1536孔培養盤中進行,且由在分析緩衝液(20mM HEPES pH 7.4,10mM MgCl2,0.015%Brij35,4mM DTT及0.05mg/ml BSA)中添加HIS-TGFβR1 T204D或HIS-TGFβR2 WT、抗HIS偵測抗體、經標記之小分子探針(Kd=<100nM;koff=<0.001s-1)及測試化合物來製備2mL反應物。將反應物在室溫下培育1小時,且在Envision培養盤讀取器上量測HTRF信號(Ex:340nm;Em:520nm/495nm)。藉由與100%抑制之無酶對照反應及0%抑制之僅媒劑反應進行比較來計算抑制資料。分析中之最終試劑濃度為1nM HIS-TGFβR1 T204D或HIS-TGFβR2 WT、0.2nM抗HIS偵測抗體、經標記之小分子探針(處於Kd)及0.5% DMSO。產生劑量反應曲線以確定抑制50%激酶活性所需之濃度(IC50)。將化合物以10mM溶解於二甲亞碸(DMSO)中,且在十一個濃度下進行評估。藉由非線性回歸分析導出IC50值。
Claims (41)
- 一種具有式(I°)結構之化合物,
- 一種具有式(I)結構之化合物,
- 如請求項2之化合物,其中Z為 式之稠合雙環,其中 (1)環A為Ar或6員Het,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;或其中Z視情況經一個或兩個-RZ基團取代。
- 如請求項2之化合物,其中 Z為、、、、、
- 如請求項2之化合物,其中 Z為、、、、或
- 如請求項2之化合物,其中 Z為、、、、、
- 如請求項2之化合物,其中 Z為、或。
- 如請求項1之化合物,其中 Z為或。
- 如請求項2之化合物,其中n為1或2,且各R1獨立地為鹵素、C1-6烷基、C1-6鹵烷基或C3-8環烷基。
- 如請求項2之化合物,其中該化合物具有式(Ia)至式(Ih)中之一者的結構:
- 一種化合物,其為:4-(6'-甲基-[2,2'-聯吡啶]-3-基)喹啉;6-(6'-甲基-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺;2,2,2-三氟乙酸6-(6'-甲基-[2,2'-聯吡啶]-3-基)喹唑啉-4-銨;甲酸6-(6'-甲基-[2,2'-聯吡啶]-3-基)喹唑啉-4-銨;6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈;6-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶;7-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶;6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺;6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈;6-([2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶;6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺;6-(6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4-胺;6-(6'-氟-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺;2,2,2-三氟乙酸6-(6'-氟-[2,2'-聯吡啶]-3-基)喹唑啉-4-銨;6-([2,2'-聯吡啶]-3-基)喹唑啉-4-胺;甲酸6-([2,2'-聯吡啶]-3-基)喹唑啉-4-銨;或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物。
- 一種具有式(II)結構之化合物,
- 如請求項12之化合物,其中Z為 式之稠合雙環,其中 (1)環A為Ar或6員Het,且環B為6員Het;或(2)環A為6員Het,且環B為5員Het;其中Z視情況經一個或兩個-RZ基團取代。
- 如請求項12之化合物,其中Z為
- 如請求項12之化合物,其中Z為
- 如請求項12之化合物,其中Z為
- 如請求項12之化合物,其中Z未經取代。
- 如請求項12之化合物,其中R1為氫或甲基。
- 如請求項12之化合物,其中該化合物具有式(IIa)至式(IIh)之結構:
- 一種化合物,其為:6-(6'-甲基-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺;2,2,2-三氟乙酸6-(6'-甲基-[2,2'-聯吡啶]-3-基)喹唑啉-4-銨;6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈;6-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶;7-(6'-甲基-[2,2'-聯吡啶]-3-基)-[1,2,4]三唑并[1,5-a]吡啶;6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺;6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺;6-(6'-氟-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺;2,2,2-三氟乙酸6-(6'-氟-[2,2'-聯吡啶]-3-基)喹唑啉-4-銨;6-([2,2'-聯吡啶]-3-基)喹唑啉-4-胺;甲酸6-([2,2'-聯吡啶]-3-基)喹唑啉-4-銨; 或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物。
- 一種醫藥組合物,其包含如請求項1至20中任一項之化合物或醫藥學上可接受之鹽及醫藥學上可接受之載劑、賦形劑或稀釋劑。
- 一種具有式(I)結構之化合物,
- 一種具有式(I)結構之化合物,
- 如請求項23之用途,其中該疾病或病症為肌肉病症、脂肪組織病症、神經肌肉病症、代謝病症、糖尿病或骨骼退化病症。
- 如請求項23之用途,其中該疾病或病症為肌肉病症。
- 如請求項23之用途,其中該疾病或病症為肌肉營養不良、肌肉萎縮症、充血性阻塞性肺病、肌肉萎縮症候群、肌肉減少症或惡病體質。
- 如請求項23之用途,其中該疾病或病症為肌肉營養不良。
- 如請求項23之用途,其中該疾病或病症為肥胖、2型糖尿病、葡萄糖耐量異常、症候群X、由外傷誘發之胰島素抗性、或骨質疏鬆。
- 如請求項23之用途,其中該疾病或病症為骨質疏鬆。
- 如請求項23之用途,其中該疾病或病症為因慢性糖皮質激素療法所致之低骨質量、性腺早衰(premature gonadal failure)、雄激素抑制、維生素D不足、繼發性副甲狀腺亢進症、營養不足及神經性厭食症。
- 一種具有式(I)結構之化合物,
- 一種具有式(I)結構之化合物,
- 一種具有式(I)結構之化合物,
- 如請求項23至30中任一項之用途,其中該患者為哺乳動物。
- 如請求項34之方法,其中該哺乳動物為人類。
- 如請求項1之化合物,其中該化合物具有式(Ii)至式(Im)、(IIi)至式(IIk)及式(III)中之一者的結構:
- 一種化合物,其為:6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(4'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-甲氧基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(4'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-(二氟甲基)-5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-(二氟甲基)-5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺3'-(3-氰基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-5-甲酸甲酯3'-(3-胺甲醯基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-5-甲酸甲酯3'-(3-胺甲醯基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-5-甲酸6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-乙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-異丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈 6-(6'-異丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-甲氧基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-環丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-環丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-(苯甲氧基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-([2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-乙醯基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-(2-羥基丙-2-基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(4',6'-二甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺N-(3'-(3-氰基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-6-基)甲磺醯胺N-(3'-(3-氰基咪唑并[1,2-a]吡啶-6-基)-[2,2'-聯吡啶]-6-基)乙醯胺6-(6'-氯-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶6-(6'-(二氟甲基)-5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈6-(6'-甲氧基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈6-(6'-甲氧基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺6-(5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈6-(5'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺6-(5'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈 6-(5'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺6-(4'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈6-(4'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈6-(6'-異丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈6-(6'-異丙基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺6-(6'-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲腈2,2,2-三氟-N-(6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-基)乙醯胺6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲酸N-(2,2-二氟乙基)-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-甲基-[2,2'-聯吡啶]-3-基)-N-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-3-甲醯胺N-(2-甲氧基乙基)-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺N-(2H3)甲基-6-[2-(6-甲基吡啶-2-基)吡啶-3-基]咪唑并[1,2-a]吡啶-3-甲醯胺甲基-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲酸6-(6'-甲基-[2,2'-聯吡啶]-3-基)-N-(氧雜環丁-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺N-環丙基-6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-b]噠嗪-3-甲醯胺 N-(6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-基)乙醯胺N-(6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-基)乙醯胺6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-甲醯胺6-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-甲醯胺6-(6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-2-甲醯胺6-(5-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(5-氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-(二氟甲基)-5-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-(二氟甲基)-5-氟-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(5,5'-二氟-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6,6'-二甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6,6'-二甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-(二氟甲基)-6-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6'-甲基-6-(三氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(6'-甲基-6-(三氟甲基)-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺3-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6'-甲基-[2,2'-聯吡啶]-4-甲酸甲酯6-(4-(羥甲基)-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈 6-(4-(二氟甲基)-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲腈6-(4-(二氟甲基)-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(6-乙醯胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺N-(3-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6'-甲基-[2,2'-聯吡啶]-5-基)乙醯胺6-(5-乙醯胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(5-胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(5-胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲酸N-(3-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6'-甲基-[2,2'-聯吡啶]-4-基)乙醯胺6-(4-胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(4-乙醯胺基-6'-甲基-[2,2'-聯吡啶]-3-基)咪唑并[1,2-a]吡啶-3-甲醯胺6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4-胺6-(5'-氟-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4-胺6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4-胺6-(6'-環丙基-[2,2'-聯吡啶]-3-基)吡啶并[3,2-d]嘧啶-4-胺6-(6'-乙基-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺6-(6'-異丙基-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺6-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺 6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺6-(6'-異丙基-[2,2'-聯吡啶]-3-基)喹唑啉-4-胺6-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)喹喏啉6-(6'-甲基-[2,2'-聯吡啶]-3-基)喹喏啉6-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)喹喏啉5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1H-吲唑5-(5'-氟-[2,2'-聯吡啶]-3-基)-1H-吲唑5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)-1H-吲唑3-(二氟甲基)-5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)-1H-吲唑5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲腈5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲腈5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲腈5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸N-甲基-5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺N-環丙基-5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺N-甲基-5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺N-環丙基-5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺5-(6'-甲基-[2,2'-聯吡啶]-3-基)-N-(氧雜環丁-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸N-環丙基-5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)-N-(氧雜環丁-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯5-(6'-(二氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶-3-甲酸5-(6'-(三氟甲基)-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶5-(5'-氟-6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶5-(6'-甲基-[2,2'-聯吡啶]-3-基)吡唑并[1,5-a]嘧啶或其醫藥學上可接受之鹽、前藥或N-氧化物,或其溶劑合物或水合物。
- 一種醫藥組合物,其包含如請求項36或37之化合物或醫藥學上可接受之鹽及醫藥學上可接受之載劑、賦形劑或稀釋劑。
- 一種具有式(I°)結構之化合物,
- 一種於活體外抑制細胞中GDF-8之方法,其包含使該細胞與有效量之化合物或其醫藥學上可接受之鹽、前藥或N-氧化物或其溶劑合物或水合物接觸,其中該化合物具有式(I)結構:
- 一種於活體外抑制細胞中GDF-8之方法,其包含使該細胞與有效量之化合物或其醫藥學上可接受之鹽、前藥或N-氧化物或其溶劑合物或水合物接觸,其中該化合物具有式(I°)結構:
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-
2016
- 2016-02-15 ES ES16711043T patent/ES2928084T3/es active Active
- 2016-02-15 WO PCT/US2016/017938 patent/WO2016133838A1/en active Application Filing
- 2016-02-15 CN CN201680022627.4A patent/CN107531666A/zh active Pending
- 2016-02-15 US US15/043,729 patent/US9981944B2/en active Active
- 2016-02-15 JP JP2017543931A patent/JP6800158B2/ja not_active Expired - Fee Related
- 2016-02-15 EP EP16711043.6A patent/EP3259264B1/en active Active
- 2016-02-19 AR ARP160100449A patent/AR103740A1/es not_active Application Discontinuation
- 2016-02-19 TW TW105104992A patent/TW201643157A/zh unknown
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EP3259264A1 (en) | 2017-12-27 |
JP6800158B2 (ja) | 2020-12-16 |
US20160264553A1 (en) | 2016-09-15 |
US9981944B2 (en) | 2018-05-29 |
EP3259264B1 (en) | 2022-07-27 |
JP2018505903A (ja) | 2018-03-01 |
AR103740A1 (es) | 2017-05-31 |
CN107531666A (zh) | 2018-01-02 |
WO2016133838A1 (en) | 2016-08-25 |
ES2928084T3 (es) | 2022-11-15 |
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